Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:21]([CH3:22])[C@H:20]4[N:17]([C:18](=[O:26])[C@@H:19]4[C@H:23]([OH:25])[CH3:24])[C:16]=3[C:27]([O:29]CC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11][N:10]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[N:5][N:4]=[N:3]1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:25][C@@H:23]([C@H:19]1[C:18](=[O:26])[N:17]2[C@@H:20]1[C@@H:21]([CH3:22])[C:15]([S:14][C@@H:12]1[CH2:11][NH:10][C@H:9]([CH2:8][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:13]1)=[C:16]2[C:27]([OH:29])=[O:28])[CH3:24]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4nnnn4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSc4nnnn4C)C3)[C@H](C)[C@H]12
Yield: 49.3 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-6-[(1R)- 1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g), 20% palladium hydroxide on carbon (0.5 g), 0.05M phosphate buffer (pH 6.3, 30 ml) and tetrahydrofuran (30 ml) was stirred for 3 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filt-rate was concentrated under reduced pressure to remove the organic solvent. The residue was washed with ethyl acetate (30 ml×2) and evaporated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (60 ml) and 10% aqueous acetone solution (120 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-{(1-methyl-1H-tetrazol-5-yl)thiomethyl}pyrrolidin-4-ylthio]-7-oxo-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.23 g).
Reaction SMILES: [Na].[N+:2]([C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl>O>[N+:2]([C:5]1[C:13]2[N:12]=[N:11][N:10]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cccc2[nH]nnc12
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1cccc2c1nnn2SC(Cl)(Cl)Cl

Procedure:
A solution of 10.2 grams of the sodium salt of 4-nitrobenzotriazole, 6 milliliters of trichloromethylsulfenyl chloride and 100 milliliters of water is stirred at 5° C. for 1 hour. The brown solid is collected by filtration and washed with ethyl ether. The crude product weighs 9.3 grams (51%) and recrystallized from carbon tetrachloride, m.p. 136.5°-137.5° C.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])[CH:5]=[CH:4]N=C1.NC1C[CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:24][C:23]1[O:22][N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]=1[C:16]1[O:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]([NH:1][CH:5]3[CH2:33][CH2:34][O:35][CH2:36][CH2:4]3)=[O:7])=[CH:13][CH:12]=2)=[N:18][N:17]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)NC3CCOCC3)cc2)o1
Yield: 46 %

Procedure:
As described for example 78c, imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) was converted using 4-aminotetrahydropyran instead of cyclopropylamine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 100 mg, 46%) which was obtained a white solid. MS: m/e=431.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][S-:35].[Na+].O>CS(C)=O>[CH:31]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([S:35][CH3:34])=[CH:3][C:4]4=[N:10][CH:9]=3)=[O:12])[N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[N:17]=2)[CH2:33][CH2:32]1
Reactant: C[S-]
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccn2c(C(=O)Nc3cccc4c3c(C3CC3)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 55 °C
Yield: 82.5 %

Procedure:
A mixture of 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (200 mg, 0.44 mmol; prepared as in Example 65, step C) and sodium methanethiolate (61 mg, 0.88 mmol) was dissolved in DMSO (2 mL). The reaction mixture was heated at 55° C. for 4 hours. The mixture was cooled to ambient temperature, transferred into water (100 mL) with stirring, and the resulting solid was collected by vacuum filtration and dried under vacuum to give the product (0.17 g). MS (ES+APCI) m/z=468.9 (M+H).
Reaction SMILES: [Li].C([Li])(CC)C.C=CC=C.C=CC1C=CC=CC=1.C1(N[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)C=CC=CC=1>CCCCCC.O>[CH:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=1[CH:34]=[CH2:35])=[CH2:26]
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Agent: C=CC=C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C=Cc1ccccc1
Solvent: O
Product: C=Cc1ccccc1C=C
Reaction time: 1 h

Procedure:
Still further, in a nitrogen atmosphere, 213 m mole as active lithium of sec-butyllithium was added to a 15 wt.% n-hexane solution of 9.5 kg of a monomer mixture comprising 1,3-butadiene and styrene in a weight ratio of 40:60, and the mixture was polymerized at 60° C. for 4 hours. After more than 99% of the monomers had been polymerized, the resulting active copolymer solution was further mixed with a 20 wt.% n-hexane solution of 19.0 kg of a monomer mixture comprising 1,3-butadiene and styrene in a weight ratio of 70:30, and the mixture was polymerized first at 70° C. for 4 hours and then at 85° C. for one hour. After substantially all of the monomer mixture had been copolymerized, the resulting final copolymer was inactivated by addition of a small amount of water. To the copolymer solution, 285 g of phenyl-β-naphthylamine was added. Thereafter, n-hexane was volatilized to obtain a non-divinylbenzene-incorporated thermoplastic elastomer in accordance with the present process (sample H), and the physical properties thereof were measured.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH:18]([OH:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>CCOC(C)=O>[CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CN(C(=O)OC(C)(C)C)CCC3O)nc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CN(C(=O)OC(C)(C)C)CCC3=O)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a round bottom flask was added tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxypiperidine-1-carboxylate (20-5) (25 mg, 0.060 mmol), DCM (1 mL), and Dess-MartinPeriodinane (27.9 mg, 0.066 mmol), and the resulting mixture was then stirred under an atmosphere of nitrogen at room temperature for 15 hours. The reaction mixture was then suspended in EtOAc, and washed with a saturated solution of Na2S2O3, followed by a saturated solution of sodium bicarbonate, then water, and finally brine. Organics dried over sodium sulfate, filtered & concentrated to give crude tert-butyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-oxopiperidine-1-carboxylate (22-1). LRMS (M+H)+: observed=417.4, calculated=417.5.
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.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[N:25]=[N:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[N:24]=[N:25][C:20]([O:19][CH2:18][C:17]([F:16])([F:31])[CH3:30])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[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)nnc1OCC(C)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(C)(F)F
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (712 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (687 mg, 2.47 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (600 mg, 2.24 mmol, Amine-78, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]([O-])=[O:22])[S:20][C:13]=12.[Li+]>>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:21]([C:19]2[S:20][C:13]3[C:14](=[N:15][CH:16]=[CH:17][C:12]=3[Cl:11])[CH:18]=2)=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCOCC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCCCN1CCOCC1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 3-morpholin-4-ylpropylamine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 340/342 (MH+); HPLC Rf: 3.45 min.; HPLC purity: 89%.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][NH:46][CH3:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([N:46]([CH3:47])[CH2:45][C:44]([OH:48])=[O:43])=[O:34])=[CH:36][CH:37]=2)=[CH:38][CH:39]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 95C and N-methylglycine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.40-13.15 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.93 (m, 6 H), 6.82 (dd, 2 H), 4.84 (s, 1 H), 4.69 (s, 1 H), 4.17 (s, 1 H), 4.05 (s, 2 H), 4.00 (m, 3 H), 3.04 (s, 2 H), 2.91 (s, 3 H), 2.85 (s, 1 H), 2.39 (s, 3 H); MS (ESI+) m/z 618 (M+H)+.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Br[CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].C([O-])=O.[Na+].C(=O)=O>C(#N)C.O>[OH:2][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C([O-])O
Reactant: CC(Br)C(=O)c1ccccc1
Agent: O=C=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(O)C(=O)c1ccccc1
Yield: 98 %

Procedure:
There was added 10.08 parts of sodium bicarbonate and about 60 parts of water to a mixture of 21.3 parts of α-bromopropiophenone, 6.8 parts of sodium formate and about 90 parts of acetonitrile. The resulting mixture was stirred vigorously for 48 hours at 65° C during which time carbon dioxide evolved. After cooling, the acetonitrile solution was separated from the aqueous layer and evaporated to dryness. The residue was dissolved into chloroform which was extracted once with water, dried over sodium sulfate, and evaporated to produce analytically pure (<98%) α-hydroxy-propiophenone. The yield of this isolated product was 77.1%,
Reaction SMILES: C(OC(=O)N[CH2:11][CH:12]1[CH2:17][CH:16]2[CH2:18][CH:14]([C:15]2([CH3:20])[CH3:19])[C:13]1=[CH2:21])C1C=CC=CC=1.[CH2:23]([SiH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24].[CH2:30]([N:32](CC)CC)C>C(Cl)Cl.[Pd](Cl)Cl>[CH3:20][C:15]1([CH3:19])[CH:14]2[CH2:18][CH:16]1[CH2:17][CH:12]([CH2:11][CH2:30][NH2:32])[C:13]2=[CH2:21].[CH2:23]([SiH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24]
Reactant: C=C1C(CNC(=O)OCc2ccccc2)CC2CC1C2(C)C
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: C=C1C(CCN)CC2CC1C2(C)C
Reaction time: 1 h

Procedure:
(6,6-Dimethyl-2-methylene-bicyclo[3.1.1]hept-3-ylmethyl)-carbamic acid benzyl ester (988 mg, 3.30 mmol) was dissolved in CH2Cl2 (20 ml) under an atmosphere of dry N2. To this solution was added triethylsilane (2.10 ml, 13.2 mmol), triethylamine (330 μl, 2.37 mmol) and palladium(II) chloride (165 mg). The reaction was then heated to reflux and stirred at this temperature for one hour. The reaction was then quenched with the addition of saturated ammonium chloride solution (3.0 ml). The reaction is then partitioned between CH2Cl2 and 0.1 N NaOH. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated under vacuum to give the titled compound along with unreacted triethylsilane: C.I. m/z 166 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:22](/[CH:21]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[O:26][CH3:27])(=[O:23])=[O:24])[CH:7]=1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1cc(Cl)ccc1S(N)(=O)=O
Yield: 100 %

Procedure:
The title compound was synthesized as described for Example 226 a) in 100% yield, starting from 2-amino-4-chlorobenzenesulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18]C(C)(C)C)=O)[CH2:14][C@H:13]2[C@@H:11]1[CH2:12]2)(C(C)(C)C)(C)C.Cl.[CH3:24][C:25]1[S:26][C:27]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:28](C(O)=O)[N:29]=1.C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>O1CCOCC1.C(Cl)Cl>[CH3:24][C:25]1[S:26][C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:28]([C:16]([N:15]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:9][OH:8])=[O:18])[N:29]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CO)c(-c2ccccc2)s1
Reaction time: 2 h

Procedure:
To a solution of 4-4 (0.175 g, 0.534 mmol) in dioxane (1.4 mL) at 25° C. was added a solution of HCl in dioxane (1.33 mL, 5.34 mmol, 4M in dioxane) and the reaction mixture was stirred 2 h. The reaction concentrated directly to afford a white solid. The white solid was resuspended in CH2Cl2 (1.4 mL) at ambient temperature and to the mixture was added 1-2 (0.141 g, 0.641 mmol), triethylamine (0.27 g, 2.7 mmol), EDC (0.154 g, 0.801 mmol) and HOBT (0.123 g, 0.801 mmol). The reaction was stirred 15 h and quenched with saturated NaHCO3 (5 mL). The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaHCO3 (3×15 mL). The combined organic phase was dried over magnesium sulfate and concentrated. The residue was purified by normal phase silica gel chromatography (0 to 100% EtOAc in hexanes, then 0 to 25% MeOH in EtOAc) to afford the product (4-5) as a foamy solid. ESI+ MS: [M+H]+ 315.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH2:31][CH:30]([C:32](Cl)=[O:33])[O:29][N:28]=2)[CH:22]=1>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH2:31][CH:30]([C:32]([NH:1][C:2]3[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=3)=[O:33])[O:29][N:28]=2)[CH:22]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CC(c2cccnc2)=NO1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of 4-aminobenzoic acid (0.020 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine, (0.020 mol) in CH2Cl2 (100 ml) was cooled to 0° C. (±)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarbonyl chloride monohydrochloride (0.020 mol) was added. The resulting brown suspension was stirred overnight. The precipitate was filtered off, washed with CH2Cl2, then dried. The filtrate was evaporated under reduced pressure. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was stirred in methanol, filtered off, then dried, yielding 2.3 g of (±)-4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]-carbonyl]amino]benzoic acid (interm. 19).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:15][CH3:16])=[C:10]2[N:13]=O)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[ClH:27]>C(OCC)C>[ClH:27].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]3[N:15]([CH3:16])[C:23]([C:22]4[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=4)=[N:13][C:10]=32)=[CH:5][CH:4]=1
Reactant: CNc1ccc2ccc(OC)cc2c1N=O
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(-c2nc3c4cc(OC)ccc4ccc3n2C)cc1
Yield: 40 %

Procedure:
The compound of the title, as the free base, is prepared by following essentially the same procedure described in example 2 but using 7-methoxy-2-methylamino-1-nitrosonaphthalene instead of 2-methylamino-1-nitrosonaphthalene and 4-methoxybenzaldehyde instead of 4-ethoxybenzaldehyde. By addition of HCl to a diethyl ether solution of the free base, the corresponding hydrochloride precipitates. Yield 40%. M.p. 265° C. dec. (from methanol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[CH:5][CH:4]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[CH:5][CH:4]=1)=[O:1]
Reactant: OCc1ccc2cnccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1ccc2cnccn12
Temperature: 25 °C

Procedure:
7.28 of 6-hydroxymethylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 18 was dissolved in 400 ml of dioxane; and 10 g of manganese(IV) dioxide was added thereto. The reaction mixture was refluxed for 30 minutes and then cooled to room temperature. The resulting solution was filtered; and the filtrate was concentrated under a reduced pressure to yield 5.3 g of title compound.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]=[C:10](Cl)[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[C:8]2[Cl:24].[C:25]([O-])(O)=[O:26].[Na+]>C1(C)C=CC=CC=1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]=[C:10]([O:26][CH3:25])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[C:8]2[Cl:24]
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
Sodium methoxide (4.29 g, 79.5 mmol) was added to a suspension of 6-bromo-2,4-dichloro-3-(3-fluorophenyl)-8-methylquinoline (3.06 g, 7.95 mmol, Intermediate 50, step c) in toluene (30 mL) in a pressure tube. The vessel was sealed and was heated in a 100° C. oil bath for 24 hours. To the mixture was added 10 wt. % aqueous NaHCO3 (60 mL), the mixture was stirred for several minutes, and the phases were separated. The organic phase was washed once with saturated aqueous NaCl. The organic phase was dried (Na2SO4), filtered, and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:36]=[CH:35][C:10]([NH:11][C:12]2[CH:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-])=O)[CH:22]=[CH:21][C:13]=2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=1>[C].[Pd].C(OCC)(=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:36][CH:35]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a mixed solution of tetrahydrofuran 10 mL and ethyl acetate 5.0 mL of tert-butyl 2-(4-fluoroanilino)-4-(2-nitroanilino)benzoate 0.35 g was added 10% palladium-carbon 74 mg, it was stirred under hydrogen atmosphere at room temperature for 4 hours and 30 minutes, and subsequently it was stirred at 34° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and solid matter was filtrated to give tert-butyl 4-((2-aminophenyl)amino)-2-(4-fluoroanilino)benzoate 0.15 g of a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]([NH2:33])[CH3:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][CH:31]([C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:21]=[CH:22][CH:23]=[N:24]5)[CH3:32])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: CC(N)c1ccc2nccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc5nccnc5c4)c3C2)c(C#N)c1
Yield: 15.3 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (200 mg, 0.70 mmol) and 1-(quinoxalin-6-yl)ethanamine (150 mg, 0.87 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (734 μL, 4.2 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light brown solid (45 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].CO.O>O1CCCC1>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[N:22][C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([CH2:11][C:5]4([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]4)(=[O:13])=[O:14])[CH2:16][CH2:17]3)=[N:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Yield: 69.5 %

Procedure:
1-{4-[5-(4-Fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-cyclohexanecarboxylic acid methyl ester (0.40 g) and lithium hydroxide monohydrate (0.20 g) were combined in tetrahydrofuran (20 ml), methanol (10 ml) and water (5 ml) and heated to reflux for 10 h. The organic solvents were then removed under reduced pressure. The aqueous residue was diluted with water (20 ml), acidified with citric acid to approximately pH 4, and a white precipitate filtered off. After drying, the precipitated solid was triturated with hot ethyl acetate (30 ml) to provide the title compound as a white solid (0.27 g, 69%).