Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=O)[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(#N)C>[CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=[N:30][CH2:26][CH2:27][CH2:28][CH3:29])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)N(CCCC)CCCC
Reactant: CCCCN
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN=C(N(CCCC)CCCC)N(CCCC)CCCC
Temperature: 0 °C
Yield: 82.9 %

Procedure:
A mixture of 56.9 grams (200 mmol.) of tetra-n-butylurea, 32.2 grams (210 mmol.) of phosphorus oxychloride and 75 ml. of acetonitrile was heated at 75° C. in a nitrogen atmosphere for one hour. The mixture was then cooled to 0° C. and 33.6 grams (460 mmol.) of n-butylamine was added over 15 minutes with stirring, whereupon a soft, fluffy precipitate formed. The mixture was warmed to 60° C. for one hour and again cooled to 0° C., quenched with 50 ml. of 25% (by weight) aqueous sodium hydroxide solution and extracted with ether. The ether extracts were dried over magnesium sulfate, filtered and stripped to give a pale yellow oil which, upon distillation, yielded 56.32 grams (83% of theoretical) of penta-n-butylguanidine.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@:15]4([CH3:25])[C@@:19](O)([C:20]([CH2:22]O)=[O:21])[CH2:18]C[C@H]4[C@@H]3CCC1=CC(=O)CC2.C[C@@]12[C@@](O)([C:37](CO)=[O:38])CC[C@H]1[C@@H]1CCC3[C@@](C)([C@H]1[C@@H](O)C2)C=CC(=O)C=3.[OH:53][C@H]1C[C@@]2(C)[C@@H](CC[C@]2(OC(=O)C)C(=O)COC(=O)C)[C@H]2[C@H]1[C@]1(C)C(CC2)=CC(=O)C=C1.Cl(O)(=O)(=O)=O>>[C:20]([CH:19]([CH2:15][CH3:25])[C:18]([O:38][CH3:37])=[O:53])(=[O:21])[CH3:22]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCC(C(C)=O)C(=O)OC

Procedure:
Hydrocortisone or prednisolone with 20-hydroxy and 20-carboxy groups are known, e.g., (III) methyl (20R)-11β,17, 20-trihydroxy-3-oxo-1,4-pregnadien-21-oate; and (III) is reacted with an alkyl acetylalkanoate or alkyl formylalkanoate in the presence of perchloric acid to produce the corresponding 17,20-carboxycyclic acetal pregnane derivatives, e.g., when methyl acetylbutyrate is used the product is (IV) methyl (20R)-11β-hydroxy-3-oxo-17,20-(methyl,methoxycarbonyl-n-propyl)methylenedioxy-1,4-pregnadien-21-oate; when methyl formylformate is used the product is (V) methyl (20R)-11β-hydroxy-3-oxo-17,20-(methoxycarbonyl)methylenedioxy-1,4-pregnadien-21-oate;
Reaction SMILES: C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.[C:19]([O:23][P:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@@:46]([CH3:54])([S:50]([CH3:53])(=[O:52])=[O:51])[C:47](O)=[O:48])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:22])([CH3:21])[CH3:20].[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][NH2:62].Cl.CN(C)CCCN=C=NCC>ClCCl.O>[P:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][C@@:46]([CH3:54])([S:50]([CH3:53])(=[O:52])=[O:51])[C:47](=[O:48])[NH:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)=[CH:42][CH:43]=2)=[CH:34][CH:33]=1)([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OP(=O)(Oc1ccc(-c2ccc(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2)cc1)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(Oc1ccc(-c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A solution of triethylamine (2.0 mL, 15 mmol, 1.8 equiv), 1-hydroxyl benzotriazole monohydrate (2.3 g, 15 mmol, 1.8 equiv), (2R)-4-{4′-[(di-tert-butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (4.4 g, 8.2 mmol, 1.0 equiv), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.4 g, 12 mmol, 1.4 equiv), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.2 g, 11 mmol, 1.4 equiv) in dichloromethane (205 mL) was allowed to stir at room temperature for 1 day. The reaction was diluted with water (600 mL) and dichloromethane (600 mL), the aqueous phase was separated and extracted with dichloromethane (2×300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60% ethyl acetate in heptane) to provide the title compound (3.29 g, 63%). MS (LCMS) m/z 638.8 (M−1).
Reaction SMILES: C1(C2C(N3CCN(C(C4C=NC(F)=CC=4C)=O)CC3)=NC=C(C)C=2)CC1.COC1C=CC(CN)=CC=1.Cl[CH2:38][CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].[NH2:45][C:46]1[N:51]=[CH:50][C:49]([C:52]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[C:65]([CH:66]4[CH2:68][CH2:67]4)=[CH:64][C:63]([CH3:69])=[CH:62][N:61]=3)[CH2:56][CH2:55]2)=[O:53])=[C:48]([CH3:70])[CH:47]=1>>[CH:66]1([C:65]2[C:60]([N:57]3[CH2:58][CH2:59][N:54]([C:52]([C:49]4[CH:50]=[N:51][C:46]([N:45]5[CH2:38][CH2:39][CH2:40][S:41]5(=[O:43])=[O:42])=[CH:47][C:48]=4[CH3:70])=[O:53])[CH2:55][CH2:56]3)=[N:61][CH:62]=[C:63]([CH3:69])[CH:64]=2)[CH2:68][CH2:67]1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C2CC2)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: COc1ccc(CN)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cc3C)CC2)c(C2CC2)c1

Procedure:
Using [4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (180 mg) described in Preparation Example 181, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.12 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (125 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13]1.O.[OH-].[Li+].CO.O>C(OCC)C>[C:23]1([C:14]2[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][N:12]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:10])=[O:9])[N:13]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCCCCCCC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A mixture of methyl 3,4-diphenyl-1H-pyrazole 1-octanoate (3.40 g, 9 mmol), lithium hydroxide hydrate (1.13 g, 27 mmol), methanol (60 mL), and water (10 mL) was heated at reflux on a steam bath. After 15 minutes, the solution was concentrated in vacuo, diluted with water and 2N HCl solution until pH=1. The mixture was extracted with methylene chloride, the combined extracts dried, and the solvent evaporated to leave an oil. Dissolution in diethyl ether followed by the addition of hexanes provided 3,4-diphenyl-1H-pyrazole-1-octanoic acid (2.80 g, 86%); m.p.=108°-110° C. MS(CI): m/e=363 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([OH:27])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23]1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:27][C:25]1[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[CH:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2F)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2F)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
K2CO3 (2.00 g) and benzylchloride (1.2 mL) were added to a solution of ethyl 1-(2-fluorophenyl)-4-hydroxypyrazole-3-carboxylate (2.47 g) in anhydrous DMF (20 mL) at room temperature, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with H2O, sat. NaHCO3 and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 1/19, 1/9, 1/4 and 1/2) to yield 3.09 g of the title compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11].C[O:13][C:14](=[O:17])[CH:15]=[CH2:16]>CO.C(OCC)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:16][CH2:15][C:14]([OH:17])=[O:13]
Reactant: C=CC(=O)OC
Reactant: COc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccccc1SCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
1.5 ml of a solution of 1N sodium hydroxide in methanol are added to a solution of 20.2 g of 2-methoxybenzenethiol in 20 ml of methanol and 20 ml of diethyl ether followed by cooling to 0° C. 13.9 ml of methylacrylate was then dropwise added to this solution. After completion of dropping, the reaction mixture was warmed to room temperature and stirred overnight. After concentrating the reaction mixture by a rotary evaporator, 8.7 g of sodium hydroxide, 100 ml of water and 35 ml of methanol was added followed by stirring vigorously overnight. The reaction mixture was acidified with concentrated hydrochloric acid while cooling and the resulting solution was extracted with chloroform. The chloroform layer was dried with magnesium sulfate, the solvent was distilled off and the resulting crystal was recrystallized from chloroform-hexane to obtain 25.4 g of the target 2-(2-methoxyphenylthio) ethanecarboxylic acid (yield: 83%, m.p.: 91°-91.5° C.).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)CBr
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21

Procedure:
A mixture of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.64 g), acetonitrile (20 ml), potassium carbonate (0.6 g) and ethyl bromoacetate (0.44 ml) is refluxed for 3 hours. The reaction solution is concentrated and water is added to the resulting residue, and the mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and recrystallized from ethyl acetate/petroleum ether to give 5-(N-methyl-N-ethoxycarbonylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.82 g) as colorless prisms, m.p. 167°-168° C.
Reaction SMILES: C1([C:7]([C@@H:29]([C@H]2OC(=O)[C@@H](C(C)C)C2)C)([C:11]2[N:15]3[CH:16]=[C:17]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[C:14]3=[N:13][N:12]=2)[C:8](N)=[O:9])CCCCC1.[NH2:40][C@@H:41]([CH2:56][CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)[C@@H:42]([OH:55])[CH2:43][C@@H:44]([CH:52]([CH3:54])[CH3:53])[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:46].[CH:63]1[CH:64]=[CH:65]C2N(O)N=[N:69][C:67]=2[CH:68]=1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[CH2:48]([NH:47][C:45](=[O:46])[C@H:44]([CH:52]([CH3:53])[CH3:54])[CH2:43][C@H:42]([OH:55])[C@@H:41]([NH:40][C:8](=[O:9])[CH:7]([C:11]1[N:15]2[CH:16]=[C:17]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[C:14]2=[N:13][N:12]=1)[CH2:29][C:68]1[CH:67]=[N:69][CH:65]=[CH:64][CH:63]=1)[CH2:56][CH:57]1[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]1)[CH2:49][CH2:50][CH3:51]
Reactant: CCCc1nc(-c2cccnc2)cn2c(C(C(N)=O)(C3CCCCC3)[C@H](C)[C@@H]3C[C@H](C(C)C)C(=O)O3)nnc12
Reactant: On1nnc2ccccc21
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1cccnc1)c1nnc2c(CCC)nc(-c3cccnc3)cn12)C(C)C
Reaction time: 8 h

Procedure:
A solution of sodium 2-[8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3-pyridyl)propionate (A) (120 mg) in water (1 ml) was added to a solution of (2S,4S,5S)-5-amino-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropylhexanamide (98 mg) in DMF (9 ml). HOBT (40.5 mg) and EDAC (115 mg) were added and the solution was allowed to stand overnight. The reaction mixture was worked up by a similar procedure to that described in Example 1, followed by flash chromatography eluting with methanol/dichloromethane (7:93 v/v) to give (2S,4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[(2RS)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionamido]hexanamide, as a foam (77 mg); NMR (d6 -DMSO/ D4 -acetic acid): 0.2-1.8 (complex m, 33H), 2.0 (m, 2H), 2.9-4.0 (complex m, 8 H), 4.9 (m, 1H), 7.4 (m, 1H), 7.5 (m, 1H), 7.9 (m, 1H), 8.5 (m, 2H), 8.7 (m, 2H), 9.3 (m, 2H); mass spectrum (+ve FAB, DMSO/m-nitrobenzyl alcohol): 697 (M+H)+, 624; microanalysis, found: C, 62.1; H, 7.9; N, 16.0%; C41H56N8O3. 2H2O requires: C, 67.2; H, 8.2; N, 15.3%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[C@@:36]([CH3:40])([C:37]([OH:39])=O)[CH2:35][O:34][C:33]1([CH3:42])[CH3:41])=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.[CH2:52]([O:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][NH2:68])=[O:66])=[CH:63][C:62]=1[C:71]([F:74])([F:73])[F:72])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>ClCCl.CN(C)C=O>[CH3:41][C:33]1([CH3:42])[N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[C@:36]([CH3:40])([C:37]([NH:68][NH:67][C:65](=[O:66])[C:64]2[CH:69]=[CH:70][C:61]([O:60][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[C:62]([C:71]([F:72])([F:74])[F:73])[CH:63]=2)=[O:39])[CH2:35][O:34]1
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 20.5 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
A 5 L round bottom flask was inerted and charged with HATU (199 g, 0.52 mol, 1.2 equiv), N,N-dimethylformamide (380 mL), and mixed. A solution of (R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid (D3A) (133.1 g, 0.43 mol, 1 equiv), dichloromethane (870 mL), and N,N-diisopropylethylamine (155 mL, 0.88 mol, 2 equiv) was charged to the flask over 15 minutes. The resulting mixture was stirred at 18 to 23° C. for 1 hour. A solution of benzohydrazide (D6) (145 g, 0.43 mol, 1 equiv) in dichloromethane (1120 mL), and N,N-Dimethylformamide (420 mL) was charged over 15 minutes then stirred at 18 to 23° C. for 1 hour. After 1 hour, TLC indicated the reaction was complete. The mixture was concentrated, partitioned between ethyl acetate (2.5 L) and water (2.5 L). The phases were split and the aqueous extracted once more with ethyl acetate (1 L). The organic phases were combined, washed with 10% w/v sodium chloride (2×1 L), dried with magnesium sulfate, filtered over Celite, and concentrated under vacuum to afford the crude product (367 g, 146% yield). The crude material was purified using a silica-gel column (2 kg) which was eluted with 5 to 25% ethyl acetate in heptane to give the title product (270 g, 108% yield, 95.9% AUC by HPLC) as a yellow oil.
Reaction SMILES: Cl[C:2]([C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[Cl:19][C:20]1[C:21]([CH2:30][CH2:31][NH2:32])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C(N(CC)CC)C>O1CCCC1>[Cl:17][C:12]1[C:11](/[C:2](/[NH:32][CH2:31][CH2:30][C:21]2[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:23][N:22]=2)=[C:3](\[C:9]#[N:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)C(C#N)=C(Cl)c1cccnc1Cl
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(C#N)=C(\NCCc1ncc(C(F)(F)F)cc1Cl)c1cccnc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 3-chloro-3-(2-chloropyridin-3-yl)-2-cyanoacrylate (0.1 g, 0.369 mmol, 1 eq.) in 5 ml of tetrahydrofuran were added 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine hydrochloride (0.106 g, 0.40 mmol, 1.1 eq.) and triethylamine (TEA) (0.112 g, 1.10 mmol, 3 eq.) at room temperature. After being stirred for 8 h at 80° C., the mixture was evaporated. The residue was diluted with AcOEt and the precipitate was filtered off. The filtrate was evaporated and the residual oil was subjected to column chromatography to give ethyl (2Z)-3-(2-chloropyridin-3-yl)-3-({2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl}amino)-2-cyanoacrylate (0.170 g, 99% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[F:14].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>>[F:14][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([O:9][CH3:10])=[CH:8][C:3]=1[CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: COc1cc(CCl)c(F)cc1[N+](=O)[O-]
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(OC)c([N+](=O)[O-])cc1F)OCC
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of 1-(chloromethyl)-2-fluoro-5-methoxy-4-nitrobenzene (Compound 130C, 1.578 g, 7.186 mmol) and triethyl phosphite (1.43 g, 8.62 mmol) was heated at 100° C. for 16 h in a sealed tube. After concentrating the reaction mixture under reduced pressure, the crude product was purified by silica gel chromatography on an ISCO combi-flash system using DCM/MeOH as eluent (100:0→95:5) to give an orange oil, 800 mg (35% yield). 1H NMR (CDCl3, 400 MHz): δ=1.30 (t, J=7.07 Hz, 6H), 3.20-3.27 (m, 2H), 3.97 (s, 3H), 4.11 (dd, J=8.08, 7.07 Hz, 4H), 7.17 (dd, J=5.94, 2.65 Hz, 1H), 7.67 (dd, J=8.72, 0.88 Hz, 1H). MS (ES+): m/z 322.09 [MH+] (TOF, polar).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24]O)(C)([CH3:22])[CH3:21].[CH2:26]1[CH2:31]CCC[CH2:27]1>[Mo](=O)(=O)=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:24][CH:20]2[CH2:22][CH2:31][CH2:26][CH2:27][CH2:21]2)[C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Reactant: C1CCCCC1
Agent: O=[Mo](=O)=O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 135 °C

Procedure:
A mixture of 10.5 grams (40.2 mmol) of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 16.1 grams (160.8 mmol) of 90% tert-butyl hydroperoxide, 600 mg of molybdenum trioxide and 60 ml of cyclohexane is placed in a Fischer-Porter pressure bottle (nitrogen atmosphere) in an oil bath. The bath temperature is gradually increased to 135° C. over a 2.25 hour period and then maintained at 135° C. for another 2.25 hours till the red color of the N-oxyl intermediate is discharged. Solids are removed by filtration. The cyclohexane solution is washed twice with water, then with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and finally concentrated under reduced pressure to obtain an oil. Purification by flash chromatography (silica gel; 100:3 heptane:ethyl acetate) affords 12.8 grams of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:14](=[O:18])[CH2:15][C:16]#[N:17])C.C(O)(=O)C.C([O-])(=O)C.[NH4+].C(N)(=O)C>C1C=CC=CC=1>[OH:18][C:14]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[C:8]([CH3:9])[C:15]=1[C:16]#[N:17]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: CC(N)=O
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2ccccc2c(O)c1C#N
Temperature: 160 °C
Yield: 40.5 %

Procedure:
Phenyl-2-propanone (24.93 g, 0.178 mol) was combined with ethylcyanoacetate (19.8 mL, 0.180 mol), acetic acid (8.0 mL, 0.14 mol), ammonium acetate (2.82 g, 0.0370 mol) and 80 mL of benzene in a round bottom flask equipped with a Dean-Stark trap and condenser cooled by a chiller. The reaction was heated to 160° C. for 4 h. The mixture was removed from heat and the trap drained so that the mixture could be concentrated by distilling off excess (˜50 mL) benzene. The solution contained crude (E)-ethyl 2-cyano-3-methyl-4-phenylbut-2-enoate. The concentrated mixture was removed from heat and heat adjusted to 240° C. Acetamide (50.9483 g, 0.862 mol) was added, and a Claisen head attached to distill any ethanol resulting while the mixture was heated at 240° C. for 60-90 minutes. The mixture was cooled to ˜100° C., and poured into room temperature water to quench the reaction. A clumpy orange solid was formed, removed by filtration and triturated with ice cold absolute EtOH. The solid was filtered off and the process repeated 4 times to harvest additional material. The resulting product was a pale yellow fine powder (13.20 g, 36% yield). 1H-NMR: (300 MHz, DMSO-d6): δ 11.28 (s, 1H); 8.24 (d, J=8.4 Hz, 1H); 7.80 (d, J=8.0 Hz, 1H); 7.62-7.58 (m, 1H); 7.52-7.48 (m, 1H); 7.34 (s, 1H); 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:24])[CH:19]=[N:18][C:17]=2[C:16]([C:30]([OH:32])=O)=[CH:15][CH:14]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>C(Cl)Cl.CO>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:30]([C:16]2[C:17]3[N:18]=[CH:19][C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH3:24])=[N:21][C:22]=3[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])=[CH:14][CH:15]=2)=[O:32])[CH:35]=1
Reactant: Nc1cccnc1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cccnc3)c3ncc(N(C)CCN(C)C)nc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylic acid (Step 85.1) and 3-aminopyridine. Title compound: ESI-MS: 555.0/557.2 [M+H]+; tR=3.16 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([NH2:14])=O.O>CN1CCCC1=O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][NH:14][C:7]2=[O:8]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: NC=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]cnc2ccc(Br)cc12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a solution of 5-bromo-2-aminobenzoic acid (7.9 g, 36.6 mmole) in N-methylpyrrolidinone (20 ml) was added formamide (7.25 ml, 182.5 mmole). The reaction mixture was heated at 150° C. for 7 hours, cooled to room temperature, poured into water (400 ml) and stirred for 15 minutes. The resulting suspension was filtered through a sintered glass funnel to collect the precipitate. The solid was dried under vacuum for 16 hrs to give 7.0 g of a tan solid. The resulting compound was characterized as follows: mass spectrometry: M/Z 226; HPLC: method A, retention time (Rt) 1.51 minutes).