Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([CH:37]1[CH2:42][C:41](=O)[CH2:40][CH2:39][N:38]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([CH:37]1[CH2:42]/[C:41](=[CH:8]\[O:9][CH3:10])/[CH2:40][CH2:39][N:38]1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccccc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C1/CCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1
Reaction time: 6 h
Yield: 34.1 %

Procedure:
Potassium tert-butoxide (4.49 mL, 1M in THF) was added over about 5 minutes to (methoxymethyl)triphenylphosphonium chloride (1.42 g, 4.15 mmol) suspended in anhydrous THF (25 mL) at 0° C. The resulting suspension was stirred at about this temperature for about 45 minutes at which time, tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (1.0 g, 3.46 mmol) dissolved in THF (5 mL) was added. The reaction mixture was allowed to warm to ambient and stir for another 6 h. The reaction was quenched by the addition of ammonium chloride solution and then taken up in EtOAc. After washing twice with water and once with brine, the organic portion was dried over magnesium sulfate, filtered and concentrated. The resulting semi-solid residue was purified via silica gel chromatography to give (Z)-tert-butyl 2-benzyl-4-(methoxymethylene)piperidine-1-carboxylate (375 mg, 34%). LCMS (APCI+) m/z 218.1 [M+H]+; Rt=4.51 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.Cl.[N:19]1([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:16][N:4]1[C:3](=[O:17])[C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[CH2:20][CH2:21]2)=[N:7][N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[C:5]1=[O:15].[CH2:25]([OH:26])[CH2:27][CH2:28][CH3:29]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Agent: Cl
Product: CCCCO
Product: Cn1c(=O)c(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn(CCCC(F)(F)F)c1=O
Yield: 19 %

Procedure:
The compound 3 (oil) is prepared from the triazine 4a and from the intermediate 6a according to the synthesis method 1 in n-butanol (yield: 19%).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[N:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[N:43][CH:42]=1>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:24][N:25]([CH:34]=[O:35])[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:47][C:44]3[CH:45]=[CH:46][N:41]=[CH:42][N:43]=3)=[O:23])[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ccncn1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccncn1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
1-Methylimidazole (39.7 μl, 0.498 mmol) was added into the solution of (55)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (100 mg, 0.249 mmol) in N,N-dimethylformamide (DMF) (1.8 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (20.24 μl, 0.262 mmol) was added dropwise at 0° C. To the reaction mixture was added 4-pyrimidinamine (26.1 mg, 0.274 mmol). After stirring for 2 h 10 min at ambient temperature, the reaction solution was purified by RP-HPLC to yield (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-4-pyrimidinyl-4,5-dihydro-1H-pyrazole-5-carboxamide (76 mg, 0.159 mmol, 64% yield). MS (ES+) m/z 478.8 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:31])[CH3:30].[CH:32]1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:29]([NH:31][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH2:1][CH3:32])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid ethylamide (53.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), ethylamine (2.0 M solution in THF, 1 mL), DPPA (85.0 mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 451; and 1H NMR (CD3OD, 400 MHz): δ 7.95 (1H, d), 7.75-7.73 (2H, m), 7.65-7.64 (1H, d), 7.42-7.40 (1H, m), 7.26-7.24 (1H, m), 4.27-4.25 (2H, q), 3.47-3.42 (2H, q), 1.42-1.39 (3H, t), 1.27-1.24 (3H, t) 2 —NH proton signals were not observed.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[N:40]=[C:41]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:42][C:43]=3[CH3:44])=[CH:33][CH:32]=2)[N:22]=1.CO>C(COC)OC.O>[CH3:20][C:21]1[N:22]=[C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[N:40]=[C:41]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:42][C:43]=3[CH3:44])=[CH:33][CH:32]=2)[C:24]([CH2:25][C:16]#[N:17])=[CH:27][CH:28]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: Cc1ccc(C=O)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc(CC#N)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a mixture of potassium t-butoxide (0.47 g) and dimethoxyethane (8 mL) was added a solution (8 mL) of toluenesulfonylmethylisocyanide (0.43 g) in dimethoxyethane at −78° C. Furthermore, a solution (8 mL) of 6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde (0.84 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel, column chromatography to give crystals (0.67 g, 79%) of 2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([C:19]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClCCCl.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:16]2[CH:15]=[CH:14][C:13]([C:19]3([C:25]4[CH:26]=[CH:27][C:28]([C:8](=[O:9])[C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=5)=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:18][CH:17]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(C2(c3ccccc3)CCCCC2)cc1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: ClCCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(C2(c3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)CCCCC2)cc1
Temperature: 80 °C
Yield: 54.3 %

Procedure:
In a 10-liters three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 703 g (4.33 mole) of iron chloride and 1.7 liters of 1,2-dichloroethane were mixed, and 732 g (3.94 mole) of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. After warming the reaction solution to 80° C., a solution of 395 g (1.67 mole) of diphenylcyclohexane in 630 milliliters of 1,2-dichloroethane was added dropwise for 3 hours and 40 minutes. After the dropwise addition was ended, the solution was stirred gently at reflux for 6 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured in 2 liters of ice, 1 liter of a 4N-HCl aqueous solution was added and then extracted with 1.5 liters of chloroform. The solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and then dried with magnesium sulfate. After removing off chloroform by a rotary evaporator, 700 milliliters of ethyl acetate was added still hot and cooled to deposit crystals. Deposited crystals were filtered off and the filtrate was treated with a silica gel column and purified by recrystallization from chloroform/ethyl acetate, to obtain 485 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)cyclohexane as crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH3:61])[C:52]=1[C:53](O)=[O:54].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:53]([C:52]1[C:56]([CH2:60][CH3:61])=[CH:57][CH:58]=[CH:59][C:51]=1[Cl:50])=[O:54]
Reactant: CCc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.5 mmol, 184 mg), HBTU (0.7 mmol, 265 mg) and 2-chloro-6-ethylbenzoic acid (0.7 mmol, 129 mg) in DMF (2 mL) was added diisopropylethylamine (1.25 mmol, 0.22 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel column chromatography using a Biotage (40m) column to afford 175 mg (70% yield) of N-[(2-chloro-6-ethylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H28ClN3O5 (M+Na) 520.1611, found 520.1613.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20]O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:24].C(Cl)[Cl:27]>C(Cl)(Cl)Cl>[ClH:24].[Cl:27][CH2:20][C:9]1[N:10]=[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:12]2[C:13](=[O:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cccc2nc(CCl)c(-c3cccc(F)c3)c(=O)n12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one (0.7141 g, 2.512 mmol, Prepared in Example 1) in chloroform (8.373 mL) was treated with SOCl2 (0.9139 mL, 12.56 mmol) dropwise at 0° C., and the reaction mixture was allowed to warm to rt with stirring. After 1 h, the mixture was concd under reduced pressure, co-evaporated three times with DCM, and dried under high vacuum to give 2-(chloromethyl)-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride as a brown solid: Mass Spectrum (ESI) m/e=303.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.O[C@H:30]1CCCNC1>>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:30][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and (S)-3-hydroxypiperidine hydrochloride to afford a brown oil. UPLC-MS (condition 1) tR=3.36 min, m/z=460.0-462.0, m/z=458.0-460.1; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.41 (m, 1H) 1.49-1.63 (m, 1H) 1.75-1.84 (m, 1H) 1.90-1.97 (m, 1H) 2.73 (dd, J=12.10, 9.17 Hz, 1H) 2.87-2.96 (m, 1H) 3.59-3.68 (m, 1H) 3.75 (d, J=12.72 Hz, 1H) 3.87-3.95 (m, 1H) 4.88 (s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](F)[CH:14]=3)[CH:11]=2)[NH:6][C:5](=[O:20])[CH:4]=1.[CH3:23]C1C=CC=CC=1B(O)O>>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:23])[CH:11]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=c1cc(C(F)(F)F)c2cc(-c3cccc(F)c3)ccc2[nH]1
Product: Cc1ccccc1-c1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1

Procedure:
This compound was made according to General Procedure XXIV in Example 406 from Compound 308 (Structure 16c of Scheme XXX, where R=H, R1=trilfuoromethyl) and commercially available 2-methylbenzeneboronic acid. Compound 742 was isolated as a white solid: 1H NMR (400 MHz, DMSO-d6) 12.42 (s, 1H), 7.68 (dd, J=9.6, 1.4, 1H), 7.53 (m, 2H), 7.33-7.23 (m, 4H), 7.04 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][NH:31][C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:16]=2)=[O:19])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: CCc1cc(-c2cc(C(=O)O)ccn2)c(C)[nH]c1=O
Product: CCc1cc(-c2cc(C(=O)NCCc3ccc([N+](=O)[O-])cc3)ccn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-4-carboxylic acid and 2-(4-nitro-phenyl)-ethyl-amine to afford the title compound. MS: m/e=407 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1cccs1
Reactant: CCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCOc1cccs1
Temperature: 25 °C

Procedure:
A mixture of 2-methoxythiophene (5.13 g, 44.93 mmol), n-C11H23OH (15.5 g, 89.87 mmol), toluene (50 mL), and p-toluenesulfonic acid monohydrate (0.85 g, 4.47 mmol) was heated to reflux under nitrogen for 19 hours. After cooling to room temperature, the reaction mixture was poured into water (150 mL), and the mixture was extracted with dichloromethane (DCM, 250 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash column on silica gel with hexane as eluent (slowly up to a hexane:DCM (8:2, v/v) mixture), leading to a colorless oil as the product (7.76 g, 67.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[N:12][C:13]([C:16]#N)=[N:14][CH:15]=1.S(=O)(=O)(O)[OH:24].[CH2:28]([OH:30])[CH3:29]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[N:12][C:13]([C:16]([O:30][CH2:28][CH3:29])=[O:24])=[N:14][CH:15]=1
Reactant: CCO
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(F)c(-c2cnc(C#N)nc2OCC(C)C)c1
Solvent: O
Product: CCOC(=O)c1ncc(-c2cc(OC)ccc2F)c(OCC(C)C)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyrimidine-2-carbonitrile (1.00 g) in ethanol (25 mL) and water (8.3 mL) was added conc. sulfuric acid (25 mL) at 0° C., and the mixture was stirred at 120° C. for 1 hr. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (284 mg) as a pale-yellow oil.
Reaction SMILES: CO[CH:3]([O:9]C)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.N1C(C)=CC(C)=CC=1C.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O>O.C(Cl)Cl>[Si:28]([O:8][C:5]1([CH2:4][CH:3]=[O:9])[CH2:6][CH2:7]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(CC1(O)CC1)OC
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)[Si](C)(C)OC1(CC=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 2.0 L RBF containing 1-(2,2-dimethoxyethyl)cyclopropanol (17.400 g, 119 mmol) was added DCM (550 ml) and the mixture was allowed to stir at 0° C. for 15 min. 2,4,6-Collidine (63.1 ml, 476 mmol) was added and the reaction was allowed to chill for 5 min before the addition of tert-butyldimethylsilyl triflate (27.3 ml, 119 mmol) over 10 min. The reaction was allowed to stir for 20 min and then analyzed by tlc which showed that all of the tertiary alcohol had been protected as its TBS ether. So, triethylsilyl trifluoromethanesulfonate (53.8 ml, 238 mmol) was added via syringe over 10 min. After 20 min, tlc showed all of the material was converted to a baseline Rf material (mixed acetal) and then water (300 mL) was added and the reaction was allowed to stir overnight. The layers were separated. The DCM was washed with dilute HCl to remove the 2,4,6-collidine. The aq. layer was back extracted with DCM. The combined organics were washed with sodium bicarbonate, brine, dried with sodium sulfate and filtered though a plug of silica gel. Desired fractions were collected to give the product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=O)[C:2]1=2.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)[C:2]1=2
Reactant: O=Cc1cccc2ccsc12
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc3ccsc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from benzo[b]thiophene-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [C:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=O)([C:5]#[N:6])[CH3:4])#[N:2].[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:17].[ClH:17].[C:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][NH:31][C@H:30]1[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:5]#[N:6])[CH3:4])#[N:2]
Reactant: COc1ccc(C(C)(C#N)C#N)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(C)(C#N)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 37 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[C:19]([CH2:18][NH:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(Cl)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(Cl)ccc1C#N
Yield: 36.7 %

Procedure:
Dissolve 2-amino-4-chlorobenzonitrile (12.9 g, 85 mmol) in anhydrous dimethylformamide (15 mL). Add potassium carbonate (7.6 g, 90 mmol) and methyl bromoacetate (7.8 mL, 90 mmol) and stir at 70° C. for 5 days. Add additional methyl bromoacetate (78 mL, 90 mmol) and continue heating for 1 day. Dilute with ethyl acetate (300 mL), wash with water, separate the organic phase and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (25% ethyl acetate/hexane). Recrystallize (hexane) to give the title compound (7 g, 36%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:28]C=2C=1.C(N=C=NCCCN(C)C)C.[OH-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[C:19](=[O:21])[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 1.5 gm (5.2 mmol) of methyl 4-benzyloxy-3-carboxybenzoate in 8 mL of DMF is added 0.85 gm (6.2 mmol) of HOBT and 1.2 gm (6.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). After 1 hr, 0.86 mL of 30% ammonium hydroxide is added, and the solution stirred for an additional 2 hr. The reaction mixture is concentrated to remove most of the DMF, and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with brine and dried over Na2SO4. Removal of solvent by rotoevaporation gives 1.37 gm (4.8 mmol) of methyl 4-benzyloxy-3-carbamoylbenzoate.