Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7](F)[C:4]=1[C:5]#[N:6]>CS(C)=O>[NH2:1][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([F:2])[C:4]=1[C:5]#[N:6]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: N
Solvent: CS(C)=O
Product: COc1cc(N)c(C#N)c(F)c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Ammonia gas was bubbled through a solution of 2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then sealed and stirred at 90° C. for 24 hours. The reaction mixture was cooled to RT and concentrated in vacuo to afford a tan residue. The residue was triturated with water, collected be vacuum filtration, and dried in vacuo to afford the title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS (ESI+) m/z=167 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[OH:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19](C)C.C(N(CC)CC)C.C1(CC(Cl)=O)C=CC=CC=1>ClCCl>[C:15]1([CH2:14][C:13]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])=[O:12])[CH:16]=[CH:17][CH:18]=[CH:19][CH:22]=1
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/COC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of geraniol and nerol (approximately 70:30 by weight) in the amount of 51.02 g (0.324 mol) and triethylamine in the amount of 33.13 g (0.324 mol) are combined with 275 mL of dichloromethane. The reaction mixture is treated with a solution of phenylacetyl chloride in the amount 51.14 g (0.324 mol) dissolved in 100 ml of dichloromethane over 1 h. After heating to reflux for 1 h, the product mixture is cooled to room temperature, washed with 100 mL of brine twice, 100 mL of saturated NaHCO3 solution twice, 100 mL of water, and dried over MgSO4. The filtrate is concentrated by rotary evaporation followed by Kugelrohr distallation. Purification of the product by column chromatography provides a colorless oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 13C and 1H NMR.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[Cs+:14].[Cs+]>CO>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cs+:14]
Reactant: O=C(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: O=C([O-])c1cccnc1

Procedure:
Nicotinic acid (0.86 g, 7 mmol) and cesium carbonate (1.14 g, 3.5 mmol) were swirled in methanol (60 ml) until a clear solution resulted. Methanol was removed in vacuo to yield cesium nicotinate as a white solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:7])[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[CH3:1][O:2][C@H:3]([C:4]1[O:6][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)[CH3:7]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CO[C@@H](C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@@H](C)c1nc(Nc2ccc(C)c(-c3cc4cnc(C)cc4n(C)c3=O)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-2-methoxypropanoic acid (40 mg, 0.4 mmol) in DMF (4 mL) were added DIPEA (65 μL, 0.4 mmol) and HATU (0.14 g, 0.4 mmol). After stirring at rt for 15 min, 17 (0.13 g, 0.4 mmol) was added as a solution in DMF (1 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 3 h. Subsequently, the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was purified by flash column chromatography on silica with DCM/2% MeOH as eluant to give (S)-3-(5-(5-(1-methoxyethyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A76) as a clear white glassy solid. 1H NMR (400 MHz, d6-DMSO) δ 9.94 (s, 1H), 8.81 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 7.40 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 4.68 (d, J=6 Hz, 1H), 3.65 (s, 3H), 3.45 (s, 3H), 2.61 (s, 3H), 2.07 (s, 3H), 1.49 (d, J=6 Hz, 3H). MS m/z 406.4 (M+1).
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][O:19][C@H:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[N+:33](=[CH2:35])=[N-:34].Cl>O1CCCC1.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:13])[NH:14][C@@H:15]1[CH2:16][CH2:17][C@@H:18]([C:21](=[O:23])[CH:35]=[N+:33]=[N-:34])[O:19][CH2:20]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)OC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)C=[N+]=[N-])OC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Ethyl chloroformate (605 μL, 6.36 mmol, 1.2 eq) is added dropwise at 0° C. to a stirred solution of (2S,5R)-5-tert-butoxycarbonylamino-tetrahydro-pyran-2-carboxylic acid (1.3 g, 5.30 mmol, 1.0 eq) and diisopropylethylamine (1.38 mL, 7.95 mmol, 1.5 eq) in tetrahydrofuran (50 mL). After 30 minutes stirring at room temperature the reaction mixture is cooled down to −20° C. before the addition of diazomethane (2.0 M solution in diethyl ether, 26.5 mL, 53.0 mmol, 10.0 eq). After 15 hours stirring at −20° C., the reaction mixture is carefully acidified to pH 6 with 1.0 N hydrochloric acid aqueous solution and then extracted with ethyl acetate (3×30 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 3:1, v/v) to afford (3R,6S)-[6-(2-diazo-acetyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a white solid (1.14 g, 80% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.[CH2:21](Br)[C:22]#[CH:23]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:23][C:22]#[CH:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCO
Reactant: C#CCBr
Product: C#CCOCCn1c(CCOC)nc2cnc3ccccc3c21
Yield: 94.2 %

Procedure:
Using the general method of Example 1 Part 2-[2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (2.53 g, 9.33 mmol) was reacted with propargyl bromide (80% in toluene, 3.11 mL, 27.9 mmol) to provide 2.72 g of 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18](Cl)=[O:19])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:31]([NH2:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18](=[O:19])[NH:37][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Cl)O2
Reactant: CCCCCCN
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCNC(=O)C1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
To one of the above aliquots of crude 2-(chlorocarbonyl)-2,5,7,8-tetramethylchroman-6-yl acetate in 10 mL CH2Cl2 was added 1.0 mL diisopropylethylamine followed by 315 mg 1-hexylamine and overnight stiffing. The reaction mixture was poured into 1.0 M citric acid and 50 mL EtOAc added. The organic layer was separated and purified by flash chromatography to give 781 mg of 2-(hexylcarbamoyl)-2,5,7,8-tetramethylchroman-6-yl acetate, as a clear syrup. MS (m/z): M+ 376.3
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1Cl.[F:22][C:23]([F:31])([F:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:27]1[CH2:28][CH2:29][CH:24]([C:23]([F:31])([F:30])[F:22])[CH2:25][CH2:26]1
Reactant: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(3,3,3-trifluoro-propyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (compound 81a; 2.0 g, 6.5 mmol), 4-trifluormethyl-piperidine×HCl (2.45 g, 13 mmol), DIPEA (4.9 mL, 29 mmol) and MeCN (25 mL) in a pressure flask at 80° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[N+:26]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[Sn]Cl.Cl>CCO>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:24])([F:23])[F:25])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:14])=[O:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 51.4 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(5-fluoro-quinolin-8-yl)-2-nitro-4-trifluoromethyl-benzenesulfonamide (Intermediate 248) (0.42 g, 1.01 mmol), SnCl2 (0.96 g, 5.06 mmol), 6N HCl (cat.) and EtOH (6 ml) at 85° C. for 24 h gave the title compound (200 mg, 52%).
Reaction SMILES: C(Cl)Cl.[NH:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:16]([OH:18])=O)[C@@H:6]([CH3:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.CCN=C=NCCCN(C)C>C(OCC)(=O)C>[NH:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:5]([C:16]([NH:26][C@H:27]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:18])[C@@H:6]([CH3:15])[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To 200 ml of methylene chloride, were added 31.0 g of Boc-Thr(Bzl)-OH and 27.6 g of Phe-OEt.HCl, and 18.3 ml of WSC were added to the mixture under cooling at 0°--5° C., which was then subjected to stirring for 2 hours at 0°--5° C. then for 18 hours at room temperature. The methylene chloride in the reaction solution was exchanged with ethyl acetate and the exchanged solution was washed successively with 1 N HCl, 5% aqueous NaHCO3 solution and water and dried over MgSO4. The organic layer was concentrated and the produced material was crystallized from hexane, which gave 39.0 g (yield=81%) of the title compound. m.p. 99°-100.5° C. [α]D25 +6.2° (C 2.7, DMF). Analysis--Calculated for C27H36O6N2 : C, 66.92; H, 7.49; N, 5.78. Found: C, 66.91; H, 7.57; N, 5.75.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[CH:18][CH:17]=1)=[O:6]
Reactant: Cc1ccc(C(CN)N2CCOCC2)cc1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(C(CNC(=O)c2cc(C)ccc2Cl)N2CCOCC2)cc1

Procedure:
From 2-chloro-5-methylbenzoic acid and 2-(4-methyl-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](S(C)(=O)=O)=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].Cl>>[C:3]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([OH:1])=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 80 °C
Yield: 103 %

Procedure:
5M NaOH (4 mL, 20 mmol) was added to 7-(3-tert-Butoxymethyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (0.398 g, 1.11 mmol) and the reaction was stirred and heated at 80° C. for 2 hours. The reaction was let cool to room temperature and HCl (−2 mL) was then added dropwise to the reaction mixture to precipitate the product (pH 1), which was filtered immediately and washed with water and dried in vacuo to afford 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (340 mg, 100%) as a brown solid. 1H-NMR (DMSO-d6): 8.64 (s, 1H), 8.21 (d, 1H, J=7.59 Hz), 8.14 (s, 1H), 7.31 (t, 1H, J=7.59 Hz), 7.18 (d, 1H, J=7.59 Hz), 6.88 (s, 1H), 6.56 (s, 1H), 4.47 (s, 2H), 1.25 (s, 9H).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:32])([F:31])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1>CO.O>[F:32][C:5]([F:4])([F:31])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: COC(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Lithium hydroxide monohydrate (9.06 g, 215.94 mmol) was added to methyl 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoate (79.58 g, 196.31 mmol) in a mixture of MeOH (800 mL) and water (400 mL). The resulting suspension was stirred at 65° C. for 16 hours. The mixture was cooled to room temperature, the methanol evaporated and the aqueous residues diluted with water (600 mL), filtered then treated with 1M citric acid until precipitation ceased. The precipitate was collected by filtration, washed with water and dried to afford 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (77 g, 101%) as a solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>C(O)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cccnc1Cl
Solvent: CC(=O)O
Product: O=C(O)c1cccnc1Nc1cc(Cl)cc(Cl)c1
Yield: 97.9 %

Procedure:
2-Chloronicotinic acid (10 g) was combined with 3,5-dichloroaniline (15 g) in 150 mL acetic acid and heated at reflux for 4 hr. Upon cooling, a white solid formed which was collected by filtration, washed with acetic acid, water, and dried to give 17.6 g of 2-(3,5-dichlorophenylamino)nicotinic acid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:3].Cl.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:38]([O:40][CH:41]([Cl:43])[CH3:42])=[O:39]>C(Cl)(Cl)Cl>[Cl:43][CH:41]([O:40][C:38]([N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:39])[CH3:42]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)NCC(O)COc1cccc2ccccc12
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)N(CC(O)COc1cccc2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of propanolol hydrochloride (3.0 g) in chloroform (100 ml) was mixed with proton sponge® (4.3 g) and cooled in an ice bath. 1-Chloroethyl chloroformate (1.5 g) was added dropwise to the reaction mixture. The suspension dissolved in about 5 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The chloroform solution was washed with water, 3N HCl and water successively. The organic layer was dried over Na2SO4 and evaporated to a thick oil weighing 3.6 g. NMR (CDCl3) δ1.25 (6H, d, J=7 Hz, CH(Me)2), 1.8 (3H, d, J=7 Hz, CH3CH), 3.3=3.6 (3H, m, ArOCH2 and CH(Me)2), 4.0-4.6 (3H, m, NCH2 and CHOH), 6.61 (1H, q, J=7 Hz, CH3CH) and 6.7-8.4 (7H, m, aromatic). IR (film) ν3450, 1715, 1583, 1270, 1248, 1108 cm-1.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([N:13]1[C:17]2[C:18]([Br:22])=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:23])(=[O:12])[CH3:11]>>[C:10]([N:13]1[C:17]2[C:18]([Br:22])=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]1=[O:23])(=[O:12])[CH3:11]
Reactant: CC(=O)n1c(=O)[nH]c2cccc(Br)c21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1c(=O)n(C(C)=O)c2c(Br)cccc21
Reaction time: 4 h

Procedure:
Sodium hydride (353 mg of a 60% dispersion in mineral oil, 8.84 mmol) and ethyl bromoacetate (1.15 mL, 8.84 mmol) were added to a solution of 1-acetyl-7-bromo-1,3-dihydro-2H-benzimidazol-2-one from Step B (1.5 g, 5.89 mmol) in DMP (20 mL) at 0° C. After 4 h, the reaction mixture was quenched with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2::EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=343 (M+1).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30].[OH-].[K+].[Cl-].[Na+]>O1CCCC1.CO.C(N(CC)CC)C>[OH:22][CH2:21][CH2:20][C:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:23])=[CH:6][CH:5]=3)[C:29]([C:25]3[O:24][CH:28]=[CH:27][CH:26]=3)=[O:30])[CH2:9][CH2:10]2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc(NC2CCN(CCC3(CCO)CCC3)CC2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCO)CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclobutyl]ethanol (synthesized in Example 66) (175 mg) in tetrahydrofuran (3 mL) was added triethylamine (0.46 mL) and 2-furoyl chloride (0.16 mL) sucessively. The solution was stirred at room temperature for 40 minutes. To the reaction solution were added methanol (4 mL) and a 3N aqueous potassium hydroxide solution (2 mL). The solution was stirred for additional 30 minutes. Saturated sodium chloride solution was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (159 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])O.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1CBr>[Ag]=O.CCOCC>[CH3:10][O:9][C:7]([CH2:6][CH:3]([O:2][CH2:1][C:20]1[CH:19]=[CH:18][CH:17]=[CH:14][C:13]=1[F:12])[CH2:4][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:8]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)CC(O)C(=O)OC
Agent: O=[Ag]
Solvent: CCOCC
Product: COC(=O)CCC(CC(=O)OC)OCc1ccccc1F
Yield: 131.4 %

Procedure:
46.4 g (0.2 mol) of silver oxide were added in portions, with constant stirring, to a mixture of 16.2 g (0.1 mol) of malic acid dimethyl ester and 57 g (0.30 mol) of 2-fluorobenzyl bromide. An exothermic reaction started slowly, and the temperature rose to 80° C. After cooling, 200 ml of ether were added, the solid was filtered off, the filtrate was concentrated and the residue was distilled at 180° C. in a waterpump vacuum. 19.6 g (72.6% of theory) of 2-(2-fluorobenzyloxy)-butane-1,4-dicarboxylic acid dimethyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]([CH:11]([CH3:15])[C:12]([OH:14])=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:16][CH:17]=1)[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:11]([CH3:15])=[C:12]2[OH:14]
Reactant: CC(C(=O)O)C(=Cc1ccc(Cl)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(C(=O)O)cc2ccc(Cl)cc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a flask containing trifluoromethanesulfonic acid (40 mL), 2-(4-chloro-benzylidene)-3-methyl-succinic acid (14.0 g) was added in portions. After being stirred at room temperature for 18 hours, the resulting mixture was poured onto ice-water, and stirred for 15 minutes. The formed precipitate was collected by filtration, and dissolved in ethyl acetate (150 mL). The solution was dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated from ethyl acetate/petroleum ether (1:10) to afford 6-chloro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (12.7 g, 97.6%) as a pink solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]=[N:4][OH:5].CC(C)([O-])C.[K+].[F:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[CH2:16][NH:17][C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=1>C1COCC1>[F:24][C:23]1[C:18]([NH:17][CH2:16][C:15]2[CH:29]=[CH:30][CH:31]=[CH:32][C:14]=2[F:13])=[N:19][C:20]([O:5][N:4]=[CH:3][CH:2]([CH3:6])[CH3:1])=[N:21][CH:22]=1
Reactant: CS(=O)(=O)c1ncc(F)c(NCc2ccccc2F)n1
Reactant: CC(C)C=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C=NOc1ncc(F)c(NCc2ccccc2F)n1
Reaction time: 0.25 h
Yield: 551.9 %

Procedure:
To a solution of 2-methylpropionaldehyde oxime (0.047 g, 0.54 mmol) in anhydrous THF (3 mL) was added a solution of potassium tert-butoxide (KOtBu, 1 M in THF; 0.50 mL, 0.50 mmol) at room temperature, and the resulting pale-yellow mixture was stirred for 15 min. To the resulting solution was added 2-fluorobenzyl-(5-fluoro-2-methanesulfonylpyrimidin-4-yl)amine (0.125 g, 0.42 mmol), and the resulting tan mixture was stirred at room temperature for 16 h. The entire reaction mixture was adsorbed to Celite (2.5 g) and the adsorbed material was purified by flash chromatography (40 g SiO2; 0→100% EtOAc/hexanes) to give 2-methylpropionaldehyde O-[5-fluoro-4-(2-fluorobenzylamino)-pyrimidin-2-yl]oxime (0.71 g, 56%) as a colorless oil: IR (thin film) 3261, 3179, 3049, 2973, 2936, 2872, 1676, 1622, 1568, 1531, 1491, 1457, 1409, 1372 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=2.5 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.43 (t, J=6.9 Hz, 1H), 7.29 (m, J=7.6 Hz, 1H), 7.09 (m, 2H), 5.42 (s, 1H), 4.76 (d, J=5.8 Hz, 2H), 2.79 (dq, J=13.9, 6.9 Hz, 1H), 1.18 (d, J=6.8 Hz, 6H); ESIMS m/z 307 ([M+H]+), 305 ([M−H]−).