Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][N:7]([CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH3:8]>C1(C)C=CC=CC=1>[CH3:6][N:7]([CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH3:8].[CH3:2][CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Agent: CN(C)CCN(C)C
Solvent: Cc1ccccc1
Product: CCCC
Temperature: 115 °C

Procedure:
Toluene 2913 g, (3.4 liters, 31.61 mol) was charged to the reactor previously heated to 115° C. The toluene is refluxed and azeotropically dried over a 4 hour period; Karl Fischer moisture analysis indicated 21 ppm of residual H2O, this toluene was dried with 1.5 g of n-BuLi solution. The dried toluene was cooled to 82° C. with the oil jacket and PID controller operating the coiling coils both set at that temperature. Upon cooling to the set point temperature, 63 g n-BuLi solution (2M in cyclohexane, 0.162 mol) was charged through the dip leg below the surface of the gently agitated (300 rpm) toluene reaction mixture. The feed line was then flushed with 75 mL of anhydrous toluene. Next, 46.4 g of TMEDA (0.399 mol) was charged to the reactor through the subsurface feed line forming the characteristic bright red color of TMEDA-complexed benzyl lithium anion with concomitant off-gassing of butane. The subsurface line was flushed with a second 75 mL aliquot of anhydrous toluene via the metering pump. Reactor agitation was increased to 510 rpm and 1713 g of styrene (99+%, 16.45 mol) dissolved in 3070 g of toluene were fed over 360 minutes. The well-calibrated metering pump was programmed to feed at a constant rate of 13.3 g/min. Anhydrous cyclohexane (2×200 mL) was charged to the styrene feed system to flush the alumina bed. The styrene feed to the reactor was deemed complete when no further heat of reaction was observed generally signified by the closing of the automated control valve on the cooling coils. The set point of PID temperature controller was maintained at 82° C. and water was fed through the cooling coils as needed while the flow of the hot oil was altered to bypass the reactor jacket. The reaction mixture was quenched at 75° C. with a 50 mL aliquot of deoxygenated water resulting in a water-white turbid mixture. The reaction mixture was washed with deoxygenated water (3×650 mL). Phase cuts were rapid and required little settling time. Water and any rag or emulsion was removed through the bottom drain valve. During the course of the 6-hour feed, an aliquot was removed after 3 hours for analysis. The GPC area % analysis (excluding unreacted toluene) was as follows: Mn=226, Mw=247 Mz=281, PD=1.091 C15H16 70.3%; C23H24 20.1%; C31H32 6.4%; and higher oligomers 3.2%. The temperature of the oil jacket was increased to 130° C. while the control valve to the cooling coils turned off. Cyclohexane, residual moisture and toluene are distilled through a simple distillation head (1 atm.) until a pot temperature of 114° C. was observed. An aliquot was removed for analysis via GPC, the composition of the reaction product mixture (a telomer distribution of this invention) was as follows: C15H16 75.7%; C23H24 17.4%; C31H32 4.7%; and higher telomers 2.2%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:7](=[O:24])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:45]([C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1)=[O:46]>C1(C)C=CC=CC=1.CCO.O.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>[CH:45]([C:47]1[CH:52]=[CH:51][C:50]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:25][C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)([CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[C:7](=[O:24])[N:8]3[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[CH:49][CH:48]=1)=[O:46]
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)c3ccc(Br)cc32)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)c3ccc(-c4ccc(C=O)cc4)cc32)cc1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
4-(6-Bromo-2-oxo-3,3-bis-pyridin-4-ylmethyl-2,3-dihydro-indol-1-ylmethyl)-N,N-dimethyl-benzenesulfonamide (306 mg, 0.517 mmol) was dissolved in a solution of 6 ml of toluene and 1 ml of EtOH under an atmosphere of dry N2. To this solution was added tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) followed by a solution of Na2CO3 (126 mg, 1.19 mmol) dissolved in 1 ml of water and 4-formylbezeneboronic acid (116 mg, 0.776 mmol). The reaction mixture was heated to 100° C. and reacted at this temperature overnight. The reaction mixture was cooled to ambient temperature and then partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was washed two more times with EtOAc. The combined EtOAc layers were dried over Na2SO4, filtered and concentrated under vacuum to give a dark oil. The oil was purified using radial chromatography eluting with MeOH/DCM (5:95) to give 258 mg of the titled compound as a solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[F:32][C:28]1[CH:27]=[C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])[CH:31]=[CH:30][CH:29]=1
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 1-bromo-3-fluorobenzene
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][CH:2]=1.[CH3:10]I>CN(C)C=O>[CH3:10][N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[CH:2][S:3][C:4]=2[CH2:5]1
Reactant: CI
Reactant: c1cc2ncsc2cn1
Solvent: CN(C)C=O
Product: CN1CCc2ncsc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiazolo[5,4-c]pyridine (1.61 g) was dissolved in N,N-dimethylformamide (50 ml), and to the solution methyl iodide (1.50 ml) was added, the resultant mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of potassium carbonate and ether were added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain the title compound (1.28 g) as a pale yellow oil.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: CC(=O)OC[C@@H]1CCCC[C@@H]1Cn1cnc2c(=O)[nH]c(N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc2c(ncn2C[C@H]2CCCC[C@H]2CO)c(=O)[nH]1

Procedure:
A solution of 9-{[1(R)-acetoxymethyl-2(S)-cyclohexyl]methyl}guanine (0.75 mmol), aqueous methanol (2 mL) and potassium carbonate (3 eq) were stirred at room temperature for 3 hours. The reaction was concentrated and the desired compound purified by silica gel chromatography (chloroform:methanol:water 90:10:1). 1HNMR (500 mHz, d6 -DMSO); 10.44 ppm (bs, 1H); 7.66 (s, 1H); 6.39 (bs, 2H); 4.46 (t, 2H); 3.90 (m, 2H), 3.55-3.30 (m, 2H, partially obscured by water); 2.18 (m, 1H); 1.8-1.1 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:51]=[CH:50][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]6[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]6)=[O:35])[C:20]5=[N:19][C:18]=4[CH3:49])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:51]=[CH:50][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:35])[N:36]6[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]6)[C:20]5=[N:19][C:18]=4[CH3:49])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of tert-butyl 4-(6-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)hexanoyl)piperazine-1-carboxylate, prepared as described in Step A, (408 mg, 0.58 mmol) in dichloromethane (5 mL), under argon, was treated with trifluoroacetic acid (435.62 μL, 5.8 mmol). After stirring for 72 h at room temperature, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution (5 mL), and the aqueous layer was extracted with dichloromethane (three times 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. (ESI-MS (M+1) 609)
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[C:42]([CH2:46][NH2:47])[CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([NH:47][CH2:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([O:33][C:32]([F:31])([F:48])[F:49])=[CH:35][CH:36]=3)[CH:41]=2)=[O:9])[CH2:5][CH2:6]1)[CH3:2]
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cccc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
A solution of acid 15A (0.30 g, 1.8 mmol) in THF (20 mL) was added with DEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 10 minutes. Then [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.308 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (45 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over an. Na2SO4 and evaporated under reduced pressure. The residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a white solid (0.15 g). Yield=28%, 1HNMR (DMSO, 200 MHz) δ 1.08 (m, 2H), 1.20 (t, 3H, J=8), 1.38 (bs, 2H), 3.42 (q, 2H), 4.38 (d, 2H, J=5.6), 7.27 (d, 1H, J=4), 7.46-7.39 (m, 6H), 7.55 (d, 1H), 7.59 (s, 1H), 7.78 (m, 2H), 7.87 (m, 2H), 8.08 (t, 1H). [M+1] 536.54 (C26H24F4N2O4S requires 536.14).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC(C)(C)C([O:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O.N1C=CC=CC=1>CN(C)C=O.O>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:14](=[O:13])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)C(=O)OC(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1cccc(O)c1

Procedure:
Pyridine (14 g, 0.18 Mol) and 4-nitrophenylacetic acid (32 g, 0.18 Mol) were stirred in toluene (100 ml) whilst trimethylacetylchloride (21 g, 0.18 Mol) was added. The toluene was evaporated to yield 4-nitrophenylacetic-trimethylacetic anhydride. 3-Aminophenol (20 g, 0.18 Mol) was stirred in DMF (100 ml) and treated with the mixed anhydride and pyridine (14 g) in dimethylformamide (DMF) dropwise. The solution was diluted with water and the product isolated by filtration and dried (19 g, 39%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1)[NH2:2].[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)[CH3:17]>>[O:15]=[C:12]1[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([NH:1][N:2]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH3:17])=[CH:8][CH:7]=2)=[N:14][NH:13]1
Reactant: CC(=O)c1ccncc1
Reactant: NNc1ccc(C2=NNC(=O)CO2)cc1
Product: CC(=NNc1ccc(C2=NNC(=O)CO2)cc1)c1ccncc1
Reaction time: 3 h

Procedure:
Analogously to Example 2 (a), from the so obtained amine there is prepared 2-(4-hydrazinophenyl)-4,5-dihydro-6H-1,3,4-oxadiazin-5-one and the suspension obtained after reduction thereof is mixed, without isolation of the hydrozine, with the 4-acetylpyridine. The reaction mixture is further stirred for 3 hours with suction and washed with water. There is thus obtained, as a crude product, 4-acetylpyridine-[4-(5-oxo-4,5-dihydro-6H-1,3,4-oxadiazin-2-yl)-phenylhydrazone]; m.p. 195° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([C:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1>CO.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([O:15][C:16]2[C:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of tert-butyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (459 mg, 1.0 mmol) and wet Pd—C (50%, 300 mg) in MeOH (20 mL) was stirred under H2 (30 psi) at room temperature overnight then the reaction mixture was filtered through and washed with MeOH. The filtrate was concentrated in vacuo to give tert-butyl 4-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyrazin-2-yl)piperidine-1-carboxylate (400 mg, 0.86 mmol, yield 86%). ESI-MS (M+1): 463 calc. for C26H31N5O3 462.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:25]4[CH:24]=[N:23][C:22]([NH2:21])=[N:27][CH:26]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.28 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as an off-white solid (0.04 g, 13%). MS (ISP) 364.0 [(M+H)+]; mp 264-266° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH:27]([NH:30][C:31]([CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1)=[O:32])([CH3:29])[CH3:28]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH:33]2[C:31](=[O:32])[NH:30][CH:27]([CH3:28])[CH3:29])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CC(C)NC(=O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NC(C)C)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 35 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with N-isopropylmorpholine-3-carboxamide (0.21 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.25 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([CH2:32][CH2:33][CH2:34][OH:35])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:11]([O:13]C(C)(C)C)=[O:12])=[O:6].C(O)(C(F)(F)F)=O>ClCl>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[C:5]([NH:7][CH2:8][CH2:9][CH:10]([C:18]1([CH2:32][CH2:33][CH2:34][OH:35])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]1=[O:31])[C:11]([OH:13])=[O:12])=[O:6]
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)c(F)c1)C1(CCCO)CCN(CCc2ccccc2)C1=O
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC(C(=O)O)C1(CCCO)CCN(CCc2ccccc2)C1=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-[(3,4-difluorobenzoyl)amino]ethyl]-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (655 mg, 1.20 mmol) in CH2 Cl2 (3 mL) is treated with TFA (2 mL) and maintained at 0° C. for 30 min. The ice bath is removed, and after 2 hours, the solution is diluted with CH2Cl2 and concentrated (3×). The residual oil is diluted with H2O (10 mL) and extracted into CH2Cl2 (3×50 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide a quantitative yield of the title compound as a white, amorphous solid:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[OH-].[Na+]>[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Product: Nc1cc(C(=O)O)ccc1C(=O)O
Reaction time: 2 h
Yield: 89 %

Procedure:
A representative preparation was done as follows: Dimethyl aminoterephthalate (5 g), cetyltrimethyl ammonium bromide catalyst (0.05 g) and aqueous NaOH solution (5%, 300 ml) were taken in a 500 ml round bottom flask, and heated to and held at about 60° C. for about 2 hours. The mixture was then cooled to about 15°-20° C., and acidified with concentrated HCl when the acid of Formula 3 separated as yellow crystals. This was filtered, washed with ice cold water, and dried (yield: 89%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc(B(O)O)cc1
Product: CCn1nc2c(c1-c1ccc(C)cc1)CCNCC2
Yield: 109.5 %

Procedure:
The title compound (136 mg) was prepared as in Example 177, Steps C and D, using 201 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 198 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C16H21N3, 255.17; found, m/z 256.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.67 (br s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.92-3.41 (m, 2H), 3.28-3.18 (m, 3H), 2.89-2.80 (m, 2H), 2.43 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](C)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][C:11]=1F.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][N:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:3](=[O:19])[C:2]=1[Br:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one(1.0 g, 3.6 mmol) was dissolved in N,N-dimethylformamide (5 mL). α-Bromo-p-tolunitrile (0.85 g, 4.3 mmol) was added followed by K2CO3 (0.59 g, 4.3 mmol). The resulting mixture was heated to 80° C. for 16 h. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate (3×100 ml). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (0.65 g, 46%). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 2H), 7.41-7.31 (m, 7H), 7.23 (d, J=7.6 Hz, 1H), 6.11 (d, J=8.0 Hz, 1H), 5.24 (s, 2H), 5.18 (s, 2H). ES HRMS m/z 395.0404 (M+H C20H15BrN2O2 requires 395.0390).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]1[N:14]=[C:13]([CH3:15])[N:12]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18](/[CH:23]=[CH:24]/[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:17]=2)[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:14]=[C:13]([CH3:15])[N:12]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C@@H:23]3[CH2:2][C@H:24]3[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:17]=2)[N:11]=1
Reactant: C[S+](C)(C)=O
Reactant: Cc1nc(/C=C/c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc([C@@H]2C[C@H]2c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsulfoxonium iodide (59.0 mg, 0.268 mmol, 1.3 eq.) in anhydrous DMSO (1.5 mL) was added sodium hydride (5.4 mg, 0.227 mmol, 1.1 eq.) and the reaction was heated to 50° C. for 30 minutes. The reaction was then cooled to room temperature and a solution of (E)-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)vinyl)quinoline (1-4) (70.0 mg, 0.205 mmol, 1.0 eq.) in DMSO (1.5 mL) was added. The reaction was stirred at room temperature for 1 hour, poured into water (5.0 mL) and extracted using ethyl acetate (3×5.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (10-40% ethyl acetate in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)quinoline (1-5) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.03 (br d, 1H, J=8.5 Hz), 7.98 (br d, 1H, J=8.4 Hz), 7.75 (br dd, 1H, J=8.0, 1.0 Hz), 7.67 (ddd, 1H, J=8.5, 7.0, 1.5 Hz), 7.60 (br s, 1H), 7.46 (ddd, 1H, J=8.0, 7.0, 1.0 Hz), 7.33 (d, 1H, J=8.5 Hz), 2.96-2.83 (m, 2H), 2.89 (s, 3H), 2.68 (s, 3H), 2.06-1.94 (m, 2H). LRMS m/z (M+H+) 357 found, 357 required. m.p. 140-141° C.