Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Br:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(=O)O
Product: Cc1nc2ccc(Br)cc2c(=O)o1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2-Amino-5-bromobenzoic acid (25 g, 116 mmol) was added in portions to acetic anhydride (150 mL) giving a slightly exothermic reaction to 30° C. The suspension was heated at reflux for 2 h. The product crystallized spontaneously upon cooling. After stirring in ice for 30 min, the crystals were filtered off and washed twice with heptane. The crystals were thoroughly dried at 0.1 mbar/50° C. One obtained 22.4 g (85%) of beige crystals. MS: m/z=239/241 (M).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=2)[CH:2]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8][N:9]=2)=[O:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2cccnc2)o1
Product: O=C(CCCCCCc1ccccc1)c1nnc(-c2cccnc2)o1
Yield: 34 %

Procedure:
Starting with methyl 5-(pyridin-3-yl)-[1,3,4]-oxadiazole-2-carboxylate and 6-bromohexylbenzene, the title compound (20 mg, 34%) was obtained as a white solid, using a procedure analogous to that described in Example 1. 1H NMR (400 MHz, CDCl3) 1.44 (m, 4H), 1.66 (quintet, J=7.5 Hz, 2H), 1.82 (quintet, J=7.3 Hz, 2H), 2.63 (dd, J=7.9, 7.3 Hz, 2H), 3.21 (t, J=7.4 Hz, 2H), 7.17-7.19 (m, 3H), 7.26-7.30 (m, 2H), 7.52 (ddd, J=7.9, 4.7, 0.6 Hz, 1H), 7.94 (dt, J=7.9, 1.9 Hz, 1H) 8.85 (dd, J=5.0, 1.8 Hz, 1H), 9.41 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.6, 28.8, 28.9, 31.2, 35.8, 35.9, 40.0, 119.4, 123.9, 125.6, 128.2, 128.4, 134.9, 142.6, 148.7, 153.4, 161.0, 164.3, 187.3; MALDI-FTMS m/z 336.1716 (C20H21N3O2+H+ requires 336.1706).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11](Cl)=[O:12])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[O:12])[CH2:7]1
Reactant: CN(C)CCCN
Reactant: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCCNC(=O)N1CCC(Oc2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A solution, 13 g (0.05 mole) of 3-(3-chlorophenoxy)-1-pyrrolidinecarbonyl chloride in 100 ml of chloroform was stirred at 0° C. for 5 min. Then, the following were added in order: 25 g of ice, 12.8 g of sodium carbonate; and 5.62 g (0.055 mole) of N,N-dimethyl-1,3-propanediamine. The resulting mixture was allowed to come to room temperature and stirred for 72 hours. At this time the reaction mixture was diluted with excess water and the organic phase separated. The chloroform solution was washed with water and extracted with 50 ml of 3N hydrochloric acid. The chloroform portion was washed with 2×25 ml of water. The hydrochloric acid portion was combined with the last 2 washes and the pH adjusted to neutral with 3N sodium hydroxide. The resulting solution was extracted with 3×30 ml of chloroform and the chloroform extracts were combined, dried over magnesium sulfate and concentrated to a dark oil, 13.2 g. All of the samples were converted to the free base, charcoaled, and chromatographed on 25 g of silica gel. Elution with chloroform gave after concentrating a dark orange oil. Trituration of this oil with ethyl ether and concentration of the triturates gave 7 g of a pale yellow viscous oil. This oil was pumped under high vacuum for 24 hours. The oil upon standing crystallized and was recrystallized from ethyl ether/30-60 petroleum ether to give 3.2 g of fine white crystals; m.p. 60°-61° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]>[C].[Pd].CO>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)/C=C/c1cccc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cccc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 46.8 %

Procedure:
Methyl(2E)-3-[3-(methylsulfonyl)phenyl]acrylate (600 mg), MeOH (6 ml) and then 10% palladium carbon (99.9 mg) were combined under N2 atmosphere. The reaction mixture was stirred at r.t. for 7 hours under H2 atmosphere (1 atm), and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/AcOEt (1:1-→1:2) as an eluent to give methyl 3-[3-(methylsulfonyl)phenyl]propanoate (283.3 mg) as colorless oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:9]([OH:13])[CH2:10][CH2:11]O>[Pd]>[OH:5][CH2:4][CH2:3][CH2:2][O:5][CH:4]([CH3:6])[CH2:3][CH2:2][C:1]([O:8][CH2:11][CH2:10][CH2:9][OH:13])=[O:7]
Reactant: CC(=O)CCC(=O)O
Reactant: OCCCO
Agent: [Pd]
Product: CC(CCC(=O)OCCCO)OCCCO
Temperature: 200 °C
Yield: 5.3 %

Procedure:
Levulinic acid (11.6 g; 0.1 mol), 1,3-propanediol (67.6 g; 0.89 mol), and 2.32 g of 10% Pd/C from Aldrich (20 wt % relative to levulinic acid) are charged to a Parr reactor, purged with nitrogen three times, heated to 200° C. with stirring, and reacted with 1000 psi of hydrogen for 20 hrs. GC analysis reveals that the reaction is complete. 1,3-Propylene glycol is distilled off at 58-59° C./0.1 mm to give 14.7 g of the crude product containing 79% of the desired monomer. The crude product (1.0 g) is chromatographed on silica gel using hexane-ethyl acetate from 3:1 to 1:1 to isolate about 0.62 g of 3-hydroxypropyl 4-(3-hydroxypropoxy)pentanoate. 1H NMR (δ, ppm, CDCl3): 1.07 d (3H, CH3), 1.66-1.80 m (6H, CH2), 2.31 m (2H, CH2CO), 3.1 (broad, 2H, OH), 3.39 m (2H, CH2O), 3.57 m (5H, 2×CH2OH, CH), 4.11 m (2H, COOCH2). 13C NMR (δ, ppm, CDCl3): 19.69 (CH3); 30.67, 31.85, 31.88; 32.68 (CH2 groups); 59.02, 61.21, 61.70, 67.06 (CH2O groups), 74.97 (CH), 174.15 (COO). Mass spectrum: m/e 234 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:26]=[C:25](Cl)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46][CH2:45]2)=[C:37]2[C:41]=1[C:40](=[O:42])[N:39]([CH3:43])[CH2:38]2>>[CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:26]=[C:25]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C@H:44]4[CH2:45][CH2:46][C@H:47]([OH:50])[CH2:48][CH2:49]4)=[C:37]4[C:41]=3[C:40](=[O:42])[N:39]([CH3:43])[CH2:38]4)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11]
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Reactant: COCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCCOC
Product: COCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCCOC

Procedure:
The title product was prepared according to the procedure for Example 102 using bis(2-methoxyethyl)(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 189A, 39.5 mg, 0.0816 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (24.7 mg, 0.0949 mmol). The reaction mixture concentrated and purified by MDP [under basic conditions; ammonium bicarbonate basic buffer (pH 9)]. The title compound was obtained as a white solid, 36.2 mg (61%). 1H NMR (400 MHz, DMSO-d6) δ 10.58 (br s, 1H), 9.89 (s, 1H), 8.46 (s, 1H), 8.65 (br s, 1H), 7.57 (br s, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.26 (dd, J=8.6, 2.0 Hz, 2H), 4.56-4.65 (m, 1H), 4.52 (s, 2H), 3.94-4.09 (m, 4H), 3.49-3.55 (m, 1H), 3.44-3.49 (m, 4H), 3.27 (d, J=13.4 Hz, 2H), 3.24 (s, 6H), 3.08 (s, 3H), 1.93 (d, J=9.9 Hz, 2H), 1.70-1.80 (m, 2H), 1.47-1.66 (m, 2H), 1.22-1.38 (m, 2H). MS (ES+): m/z 708.26 (100) [MH+]. HPLC: tR=3.61 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:9]=1)[NH2:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:27](Cl)(=[O:29])=[O:28])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][S:27]([NH:6][C:5]2[CH:7]=[C:8]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:29])=[O:28])=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 90.9 %

Procedure:
3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (822 mg, 3.29 mmol), was treated with (4-fluorophenyl)methanesulfonyl chloride (1.03 ml, 4.93 mmol) according to the method described in Preparation 15b to give 1.26 g (94% yield) of the title compound. Purity 97%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:24]=[C:25]1[O:29][C:27](=[O:28])[CH2:26]1>C(O)(=O)C>[CH2:16]([O:15][C:13]([C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:25]([OH:29])([CH3:24])[CH2:26][C:27](=[O:28])[N:6]1[CH2:5][C:4]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=1[O:2][CH3:1])=[O:14])[CH3:17]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C(NCc1ccc(OC)cc1OC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)N(Cc2ccc(OC)cc2OC)C(=O)CC1(C)O
Yield: 59.3 %

Procedure:
39.6 g (0.122 moles) of diethyl (2,4-dimethoxy-benzyl-amino)-malonate prepared according to Example (1c) are boiled with 12.3 g (11.2 ml, 0.146 moles) of diketene in 80 ml of glacial acetic acid for half an hour. The glacial acetic acid is distilled off on water bath, in vacuo, the residual oil is crystallized by trituration with 150 ml of water, whereupon the substance is dissolved in 60 ml of ethyl acetate and recystallized by addition of petroleum ether. 29.6 g (60%) of diethyl-N-(2.4-dimethoxybenzyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof are obtained. Melting point: 106° to 107° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.O>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:28][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: CCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (25.0 g) synthesized in Example 3 and heptylamine (10.0 g) were dissolved in dichloromethane (250 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (18.0 g) and hydroxybenzotriazole (HOBT) monohydrate (16.6 g) were successively added thereto, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (30.0 g) as a slightly yellow oil.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH:7]1[NH:11]C(=O)N[C:8]1=[O:13]>O>[NH2:11][C@H:7]([C:8]([OH:13])=[O:1])[CH2:6][CH2:5][S:4][CH3:3]
Reactant: CSCCC1NC(=O)NC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CSCC[C@H](N)C(=O)O
Reaction time: 0.42 h
Yield: 21.4 %

Procedure:
A mixture of 13.1 g of 98% sodium hydroxide pellets (0.32 mole) and 17.4 g (0.10 mole) of 5-(beta-methylmercaptoethyl)-hydantoin in 100 ml of water-saturated n-hexanol was heated to boiling over 25 minutes and refluxed with stirring for 26 minutes, after which the reaction mixture was quenched. The cold reaction mixture was stirred with 75 ml water for 1/4 hour, and the aqueous phase was separated. The organic phase (n-hexanol) was washed with four 25 ml portions of water. The combined, filtered, aqueous phases were neutralized to pH of 6 with concentrated hydrochloric acid, stirred at room temperature for the crystallization of methionine, and stored at 5° C. The reaction product was collected, washed with water, and dried to give 3.2 g of methionine, m.p. 268° C. decomposition. The combined mother-liquor and washings were concentrated to about 80 ml during which methionine crystallized. After the mixture had been chilled at 5° C., the reaction product was collected, washed with water, and dried to obtain 3.5 g of methionine, m.p. 268° C. decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.O.[NH2:35][NH2:36].C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:35][NH:36]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.6 %

Procedure:
A mixture of crude N-({(2R,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)benzamide (0.23 mmol theoretical) and hydrazine monohydrate (0.25 mL, 5.14 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 15 hours. The mixture was cooled, poured into saturated aqueous NaHCO3 (15 mL), and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were concentrated in vacuo, taken up in a small amount of CH3OH, and added to saturated aqueous NaHCO3 (25 mL). That mixture was extracted with 90/10 CH2Cl2/IPA (3×25 mL), and the extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (47 mg) as a pale yellow solid. LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 2.73-2.91 (m, 1H), 3.39-3.55 (m, 2H), 3.57-3.71 (m, 2H), 3.73-3.83 (m, 1H), 4.08-4.74 (bs, 2H), 5.39 (s, 2H), 6.14 (s, 2H), 6.57 (s, 1H), 7.45-7.51 (m, 2H), 7.51-7.60 (m, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.95 (s, 1H), 8.68 (t, J=5.5 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[CH:16][CH:17]=[C:7]2[C:6]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]4[CH:15]=[CH:16][CH:17]=[C:7]4[C:6]3=[O:18])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=c1c2cccn2c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c2cccn2c2ccccc2n1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg; 0.38 mmol) was added to a 5 mL microwave vessel containing a magnetic stir bar. 4-(4-Chlorophenyl)piperidin-4-ol (89.3 mg; 0.42 mmol), potassium carbonate (78.77 mg; 0.57 mmol), and 2 mL of acetonitrile were added to the vessel. The vessel was sealed and heated to 140° C. for 1 hour, after which the solvent was evaporated and the reaction mixture was purified by flash chromatography to yield 5-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (48.5 mg; 0.11 mmol; 29%). [M+1]+=436.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1.[CH:17]([N-]C(C)C)(C)C.[Li+].CI>>[F:1][C:2]1[C:7]([CH3:17])=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1
Reactant: CC1(C)COC(c2cc(F)c(F)cc2F)=N1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Product: Cc1c(F)c(F)cc(C2=NC(C)(C)CO2)c1F

Procedure:
The 2-(2,4,5-trifluorophenyl)-4, 4-dimethyl-2-oxazoline was also treated with lithium diisopropylamide followed by methyl iodide to give 2-(2,4,5-trifluoro-3-methylphenyl)-4,4-dimethyl-2-oxazoline. This intermediate was, in turn, treated with lithium diisopropylamide, then with methyl iodide, to give 2-(2,4,5-trifluoro-3,6-dimethylphenyl)-4,4-dimethyl-2-oxazoline. Hydrolysis of the oxazoline gave 2,4,5-trifluoro-3,6-dimethylbenzoic acid, which was elaborated into 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid in the usual manner.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)#[CH:31]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][CH:29]=[C:4]([N:1]3[CH:31]=[C:30]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1c(NC(=O)c2cccc(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cccnc1
Product: COc1c(NC(=O)c2cccc(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 16 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-benzamide and 3-ethynyl pyridine in the same manner as Example 15. ESI MS m/z 521 [C26H28N6O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperazine-1-carboxylate (0.0642 g, 0.164 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0264 g, 0.180 mmol) and piperidine (0.0112 g, 0.131 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperazine-1-carboxylate (0.0393 g, 46%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([NH2:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CC(O)C>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][NH:21][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)O)c(NCc2ccco2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.71 g) in 2-propanol (10 ml) were added furfurylamine (714 mg) and diisopropylethylamine (950 mg), and the mixture was stirred at room temperature for 10 min. The reaction mixture was poured into 2% aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was collected by filtration. The precipitate was dissolved in ethanol (10 ml), 2 M aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was adjusted to pH 3 with 1 M hydrochloric acid, and the precipitated crystals were collected by filtration to give the object compound (1.75 g) as a powder.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:32]([NH2:34])[CH3:33])[CH:20]=[N:21][C:22]=1[N:23]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[N:24]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:34]([CH:32]([C:19]3[CH:20]=[N:21][C:22]([N:23]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[N:24]4)=[C:17]([CH3:16])[CH:18]=3)[CH3:33])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1-n1cc(C(F)(F)F)cn1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1-n1cc(C(F)(F)F)cn1
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (200 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (240 mg, 0.79 mmol, Amine-47, single enantiomer) in a similar manner to Intermediate-2.