Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:43](=[O:44])[C:42]3[CH:46]=[CH:47][C:39]([Cl:38])=[CH:40][CH:41]=3)=[CH:17][C:16]=2[CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
[3-(4-Amino-2-phenylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.9 mmol) and triethylamine (1 mL) were combined in CH2Cl2 (10 mL). 4-Chlorobenzoyl chloride (0.29 mL, 2.3 mmol) was added, and the reaction was stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound, which was used directly in the hydrolysis step.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].[CH:21](=O)[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24].B.[Na]>CO.C(OCC)C>[CH2:1]([NH:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH:16][CH2:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)[C@H](C)N
Reactant: O=Cc1ccccc1O
Agent: B
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)[C@H](C)NCc1ccccc1O
Reaction time: 1 h

Procedure:
L-alanine laurylamide (25 g) and 1 g of sodium hydroxide were dissolved in 20 ml of methanol. To the solution were added 1.0 ml of salicylaldehyde and 0.1 g of sodium boron hydride in this order. After the mixture was stirred for 1 hour, 1.0 ml of salicylaldehyde and 0.1 g of sodium boron hydride were added thereto again in this order. After the resulting mixture was stirred overnight at room temperature, the insoluble matter was separated through filtration, and the residue was adjusted to a pH of 7 with hydrochloric acid. The oil was obtained through concentration under reduced pressure was dissolved in diethyl ether, washed with water, and then dried over magnesium sulfate. After the drying agent was separated through filtration, the filtrate was concentrated under reduced pressure to obtain 3 g of N-(2-hydroxybenzyl)-L-alanine laurylamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: BrC=Cc1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2ccccc2)CCN(C)C1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol), β-bromo styrene (91 mg, 0.55 mmol), CuI (9 mg, 0.05 mmol), L-proline (11 mg, 0.1 mmol) and potassium phosphate (212 mg, 1 mmol) taken in DMF (3 mL) under inert atmosphere, heated overnight at 80° C. The reaction mixture was cooled to RT, quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford 35 mg of title compound as the free base. 1H NMR (CDCl3, HCl salt) δ (ppm): 7.60-7.55 (d, 1H), 7.50-7.45 (m, 3H), 7.42-7.38 (m, 2H), 7.25-7.20 (m, 2H), 7.15-7.10 (d, 1H), 6.80-6.75 (d, 1H), 3.75 (s, 2H), 3.12-3.05 (m, 2H), 2.98-2.90 (m, 2H), 2.67 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:4]1([C:5]([OH:6])=[C:7]([N+:20]([O-:22])=[O:21])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O

Procedure:
U.S. Pat. No. 2,945,890 to Allan shows a method of preparing 2,4-dinitroresorcinol using a sulfuric acid/nitric acid nitrating solution. Apparently, however, styphnic acid (2,4,6-trinitroresorcinol), an undesirable and explosive side product, is also produced in fairly substantial quantities.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([O:8][CH2:18][CH3:19])=[O:7])=[CH:4][C:3]=1[OH:12]
Reactant: CCO
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(O)c(Br)c(O)c1

Procedure:
A mixture of 4-bromo-3,5-dihydroxybenzoic acid (45.0 g), concentrated sulfuric acid (5 mL), and ethanol (300 mL) was heated to reflux for 24 hours. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline in this order. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane to obtain the title compound (48.3 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(=O)C)C.[ClH:57]>C(OCC)(=O)C.ClCCCl.C(O)(=O)C>[ClH:57].[ClH:57].[ClH:57].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:29]([CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:30][C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: c1cncc(CCNCc2ccncc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde(0.92 g) and acetic acid(0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of (2-pyridine 3-ylethyl)pyridin-4-ylmethylamine(0.81 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride(0.90 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=100:0→90:10). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound(0.83 g) as a white solid
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:25][C:21]1[C:20]([I:26])=[CH:19][C:18]([C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)=[CH:23][C:22]=1[I:24]
Reactant: COC(=O)CBr
Reactant: Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
4-(Benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diiodo-phenol (0.543 g, 0.94 mmol), methyl bromoacetate (0.181 mL, 1.88 mmol), potassium carbonate (0.141 g, 1.03 mmol) and N,N-dimethylformamide (5.4 mL) were combined and stirred at ambient temperature for 1 h. The reaction mixture was added to water and filtered. The solid was washed with water and dried in vacuo to provide the (4-benzo [b]naphtho[2,3-d]thiophen-11-yl-2,6-diiodo-phenoxy)-acetic acid methyl ester as a white solid (0.537 g, 88%): mp 203-205 ° C. Aqueous potassium hydroxide (0.5 N, 2.54 mL, 1.28 mmol) was added to a stirred solution of this methyl ester (0.55 g, 0.85 mmol) in THF (5.0 mL) at ambient temperature. After 1 h the solution was concentrated, diluted with water (75 mL) and acidified with 10% aqueous HCl. The solid was filtered and washed with water to provide the title compounds as a white solid (0.428 g, 80%): mp 250-252° C.: NMR (DMSO-d6); δ8.66 (s, 1 H), 8.07 (d, J=8 Hz, 1 H), 8.01 (d, J=8 Hz, 1 H), 7.93 (s, 2 H), 7.61 (ddd, J=8, 7, 1 Hz, 1 H), 7.54-7.48 (m, 2 H), 7.47 (ddd, J=8, 7, 1 Hz, 1 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1 H), 4.69 (s, 2 H); MS (EI): 636 (100%, MI); Anal. Calc. for C24H14I2O3S: C, 45.31, H, 2.22, N, 0.00. Found: C, 44.95, H, 1.99, N, 0.23.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a stirred solution of 6-aminonicotinic acid (1 g, 7.24 mmol) in dimethylformamide (50 mL) was added 1-benzylpiperazine (1.258 mL, 1.276 g, 7.24 mmol), triethylamine (2.018 mL, 1.465 g, 14.48 mmol), 1-hydroxybenzotriazole hydrate (1.109 g, 7.24 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.388 g, 7.24 mmol). After being stirred overnight at room temperature the reaction mixture was concentrated under vacuum. Purification by silica chromatography (eluting with 5% methanol/dichloromethane) gave the title compound (1.8 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([Cl:27])[CH:18]=4)[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)CCC>[Cl:27][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH:5]=[CH:4][N:3]=[C:2]4[N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)[N:16]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Solvent: CCCCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCN(C(=O)OC(C)(C)C)CC5)nccc34)no2)cc1Cl

Procedure:
1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg), 1,1-dimethylethyl 1-piperazinecarboxylate (93 mg) and n-butanol (0.5 ml) were heated under microwave irradiation at 180° C. for 1 h. After cooling the reaction mixture was filtered and the title compound was isolated as a white solid (24 mg).
Reaction SMILES: [C:1]12[C:7](=[N:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]([NH2:16])([CH3:15])[CH3:14]>CN(C)C=O>[NH2:6][C:7]1[N:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])=[O:4]
Reactant: CC(C)N
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccnc1N

Procedure:
In addition to being useful as discussed above, acid anhydrides produced by the method of the invention are useful as intermediates for the production of pyrimidine diones which can be used as herbicides. For example, 3-azaisatoic anhydride can be dissolved in dimethylformamide and reacted with a substantially stoichiometric amount of isopropyl amine to produce 2-amino-N-isopropylnicotinamide. The reaction is conveniently conducted at a temperature of about 45°-50° until carbon dioxide evolution ceases. The 2-amino-N-isopropylnicotinamide can then be reacted with phosgene to produce 3-isopropyl pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. This reaction can be conducted under ambient pressure in p-dioxane as a solvent, preferably in the presence of triethylamine as an HCl absorber, at a temperature in the vicinity of 100°.
Reaction SMILES: [CH2:1]=O.[Na].[Br-].[O:5]([CH2:12][C:13]([NH:15][C@@H:16]1[C:51](=[O:52])[N:18]2[C:19]([C:43]([O:45][CH2:46][C:47]([Cl:50])([Cl:49])[Cl:48])=[O:44])=[C:20]([CH2:23][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:21][S:22][C@H:17]12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[O:5]([CH2:12][C:13]([NH:15][C@@H:16]1[C:51](=[O:52])[N:18]2[C:19]([C:43]([O:45][CH2:46][C:47]([Cl:49])([Cl:48])[Cl:50])=[O:44])=[C:20]([CH:23]=[CH2:1])[CH2:21][S:22][C@H:17]12)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: C=O
Agent: [Br-]
Agent: [Na]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 17 %

Procedure:
40% -Aqueous formaldehyde (24 ml.) and 3% -sodium hydrogne carbonate solution (80 ml.) were added to a solution of [7β-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonyl)ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (4.93 g, 6 mmole) in methylene chloride (40 ml.). The two-phase mixture was stirred vigorously for 2 hours and the organic phase was washed with water (100 ml.), dried (MgSO4), and evaporated to an orange foam. This foam was chromatographed on Kieselgel G (Merck; 150 g) with methylene chloride and 0.5%-acetone in methylene chloride as eluants. The appropriate fractions were combined and evaporated to a colourless oil which crystallised on addition of ether. The solvent was removed to give the title ester as a white solid (0.50 g, 17%), m.p. 136°to 140° (decomp), [β]D23 - 33° (c 1.01; Me2SO), λmax. (EtOH), 296 nm (ε 12,100), νmax. (Nujol) 3300 (NH), 1764 (azetidin-2-one), 1716 (CO2R), 1668 and 1509 (CONH) and 920 cm-1 (=CH2), τ(Me2SO-d6) 0.81 (1H, d, J 8 Hz; NH), 2.67 and 2.99 (2H and 3H, 2m; C6H5O), 3.01 (1H, dd, J 11 and 18 Hz; CH=CH2), 4.19 (1H, dd, J 8 and 5 Hz; C7 --H), 4.24 (1H, d, J 18 Hz) and 4.55 (1H, d, 11 Hz) (CH=CH2), 4.71 (1H, d, J 5 Hz; C6 --H), 4.79 and 5.01 (2H, AB-q, J 12 Hz; CH2CCl3), 5.36 (2H, s; C6H5OCH2), 5.98 and 6.34 (2H, AB-q, J 18 Hz; C2 --H2).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[C:3]([C:12](=[O:23])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(C(F)(F)F)c2)[nH]c2cc(Cl)ccc12
Product: CC(C)CC(=O)Nc1c(C(=O)c2cccc(C(F)(F)F)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-trifluoromethylbenzoyl)indole (Example 49) and isovaleryl chloride. m.p.: 179-180° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[CH3:5][C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([NH:15][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[CH2:13][CH2:14]1)=[O:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 120 °C

Procedure:
To a flask charged with toluene (37.3 mL) were added trans-N-boc-1,4-cyclohexanediamine (2.00 g, 9.33 mmol), potassium carbonate (1.290 g, 9.33 mmol) and 2-fluoro-3-nitropyridine (commercially available from Matrix Scientific, Columbia, S.C.) (1.326 mL, 9.33 mmol). The resulting bright yellow solution was heated overnight at 120° C. leading to conversion to the desired product as the primary species along with a more polar impurity according to LC-MS. The mixture was diluted with water, transferred to a separatory funnel and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure providing a bright yellow solid which was triturated with DCM providing tert-butyl ((1r,4r)-4-((3-nitropyridin-2-yl)amino)cyclohexyl)carbamate (1.51 g, 4.49 mmol, 48.1% yield) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.49 (dd, J=1.8, 4.5 Hz, 1H), 8.41 (dd, J=1.8, 8.4 Hz, 1H), 8.06 (d, J=7.7 Hz, 1H), 6.79-6.69 (m, 2H), 4.13-4.00 (m, J=3.9, 7.4, 7.4, 11.3 Hz, 1H), 3.29-3.20 (m, 1H), 2.01-1.92 (m, 2H), 1.82 (d, J=10.6 Hz, 2H), 1.55-1.41 (m, 2H), 1.38 (s, 9H), 1.35-1.21 (m, 2H). m/z (ESI) 281.2 (M+H)+.
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH:14]1[OH:23])[CH2:20]2.ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:40][C:41]1[C:42](F)=[CH:43][C:44]([F:56])=[C:45]([CH:55]=1)[C:46]([NH:48][S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51])=[O:47]>>[CH:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH:14]1[O:23][C:42]1[C:41]([Cl:40])=[CH:55][C:45]([C:46]([NH:48][S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51])=[O:47])=[C:44]([F:56])[CH:43]=1)[CH2:20]2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1C2CC3CC(C2)CC1C3
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with adamantan-2-ol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide (as prepared in Example 31), the title compound was obtained as a colorless solid (0.21 g, 38%): 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.33 (d, J=12.5 Hz, 1H), 4.81 (s, 1H), 2.87 (s, 6H), 2.08-2.03 (m, 4H), 1.84-1.71 (m, 8H), 1.54-1.50 (m, 2H); MS (ES−) m/z 429.2, 431.2 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: CSc1ccc(Br)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reaction time: 3 h

Procedure:
Place 6-methoxy-1-tetralone (1 eq.), 4-bromothioanisole (2.5 eq.), palladium acetate (0.01 eq.), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.02 eq.) and toluene in a 3 neck flask equipped with a mechanical stirrer, reflux condenser, nitrogen purge and a temperature probe. Add sodium tert-butoxide (4 eq.) and heat the slurry to reflux. After about 2-4 hours, cool the reaction to room temperature and add 3M aqueous HCl along with tetrahydrofuran. Stir the biphasic reaction mixture for 30 minutes before filtration and separation of the layers. Concentrate the organic layer to isolate 6-methoxy-2-(4-methylthiophenyl)naphthalene-1-ol by filtration.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([NH2:17])(=[O:16])[C:14]#[CH:15]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:14]([C:13]([NH2:17])=[O:16])[CH:15]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: C#CC(N)=O
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: NC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Yield: 13.1 %

Procedure:
4.8 g (0.03 mole) of 3-diazooxindole and 2.4 g (0.035 mole) of the propiolamide are taken up in benzene (250 ml) and refluxed overnight under a stream of nitrogen. The light tan precipitates that form are filtered off and dried in a vacuum oven for 4 hours. Yield: 4.4 g. Additional refluxing of the filtrate gives 900 mg of product. Total yield: 5.3 g (77.4%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1

Procedure:
To a 500 ml, 3-necked round bottom flask were added 92 g (500 mmole) p-aminodiphenylamine, 61 ml (600 mmole) cyclohexanone, 82 ml (800 mmole) nitrobenzene, 120 ml xylene solvent and 1.0 g of 5% palladium on carbon catalyst (0.05 g Pd). Using essentially the procedure of Example 1 the reaction was (A) carried out without acid and then again (B) in the presence of 3 millimoles of sulfuric acid. Reaction (B) provided about 40% (mole) more yield of DPPD over reaction (A) after 7 hours at reflux.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[S:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=3)[CH:3]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)s1

Procedure:
5-{3-[4-(5-Chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.31 g, 0.74 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.28 g, 0.81 mmol) according to the general procedure III. Obtained as light yellow oil (0.23 g), which was subsequently deprotected.