Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]([I:27])=[C:13]([C:25]=1[I:26])[C:14]([NH:16][CH2:17][CH:18]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[OH:19])=[O:15])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+].[C:46](OCCBr)(=[O:48])[CH3:47]>CC(N(C)C)=O>[OH:24][CH:21]([CH2:22][OH:23])[CH2:20][CH:18]([OH:19])[CH2:17][NH:16][C:14](=[O:15])[C:13]1[C:25]([I:26])=[C:9]([N:8]([CH2:47][CH2:46][OH:48])[C:6](=[O:7])[CH2:5][OH:4])[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]=1[I:27]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(NCC(O)CC(O)CO)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(N(CCO)C(=O)CO)c1I
Temperature: 25 °C

Procedure:
5-Acetoxyacetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 3, Step B, (89 g, 0.1 g-mole) is mixed with K2CO3 (27.6 g, 0.2-g mole) and 2-bromoethyl acetate (33.4 g, 0.2 g-mole) in DMAc (200 ml). The mixture is stirred at 35°-40° C. until the reaction is complete (approximately 8-12 hours). The solution is then cooled to room temperature and the inorganic salts are filtered. The filtrate is then evaporated under vacuum at 70° C. to yield a thick oil. The oil is triturated with isopropyl alcohol to dissolve the residual DMAC and bromoethyl acetate. The supernatant is decanted and the residual solid is evaporated to dryness to provide the desired product.
Reaction SMILES: C[O:2][CH:3]1[CH:7]([CH:8]=O)[CH2:6][CH:5](OC)O1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:12]1([S:18]([N:21]2[CH:5]=[CH:6][C:7]([CH:3]=[O:2])=[CH:8]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COC1CC(C=O)C(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccn(S(=O)(=O)c2ccccc2)c1
Yield: 88.2 %

Procedure:
A solution of 5.91 g (0.037 mol) of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde, 5.80 g (0.037 mol) of phenylsulfonamide and a spatula tip of 4-toluenesulfonic acid in 50 ml of toluene was refluxed with a water trap until water no longer separated out. The reaction mixture was washed three times with water. The organic phase was dried over magnesium sulfate with addition of activated carbon and silica gel and concentrated in vacuo. 7.68 g of a brown resin were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>C(OCC)C>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CC(C)c1ccc(N=C=O)cc1
Agent: [Na]
Solvent: CCOCC
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1
Reaction time: 0.03 h
Yield: 87 %

Procedure:
To a solution of 1-benzylindolin-5-ol (1.50 g, 6.66 mmol) in 33 mL of diethyl ether (5 mL/mmol) was added a piece of sodium (1 mg to 10 mg) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, 4-isopropylphenylisocyanate (1.3 mL, 8.0 mmol, 1.2 equivalent) was added with additional stirring for 5 min to 10 min. After removal of sodium, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 0/100) to obtain the title compound (2.24 g, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:48]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 71 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and benzoyl chloride as the starting materials in 71% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z=567.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][CH:29]1[NH:33][C:32](=[O:34])[CH2:31][CH2:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:33]3[CH:29]([CH3:28])[CH2:30][CH2:31][C:32]3=[O:34])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 43.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 110 and 5-methylpyrrolidin-2-one (198 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (412 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]2)=[CH:7][C:6]([NH2:16])=[C:5]([NH2:17])[CH:4]=1)#[N:2].[C:18](O)(=[O:22])[C:19](O)=[O:20].Cl>>[C:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1)[NH:16][C:19](=[O:20])[C:18](=[O:22])[NH:17]2)#[N:2]
Reactant: O=C(O)C(=O)O
Reactant: N#Cc1cc(N)c(N)cc1-n1ccc(=O)cc1
Agent: Cl
Product: N#Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1-n1ccc(=O)cc1
Yield: 66 %

Procedure:
First, a mixture containing 246 mg of 4-cyano-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, 294 mg of oxalic acid, and 5 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 2 hours. The mixture was cooled and precipitated crystals were filtered. Then, 284 g of the crude crystals thus obtained were further recrystallized with 2N hydrochloric acid to give 201 mg of 6-cyano-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([OH:18])=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[N:19]1([CH2:25][CH2:26]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(O)C>CC(C)=O>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: COc1c(NC(C)=O)c(O)c(OC)c2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1c(NC(C)=O)c(OCCN2CCCCC2)c(OC)c2occc12

Procedure:
A mixture of 25.1 g (0.1 mole) of 5-acetamido 4,7-dimethoxy 6-hydroxy benzofuran, 22.2 g (0.15 mole) of 2-piperidino chlorethane and 41.6 g (0.3 mole) of potassium carbonate in 250 ml of acetone was brought to reflux for 2 hours. Then it was filtered, the solvent evaporated, the residue obtained was taken up again in acetone and 20 ml of 7 N hydrochloric ethanol were added. It was filtered and recrystallized in 400 ml of propanol.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:11][C:12](=[O:38])[C@H:13]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([C:49]1[CH:50]=[CH:51][C:52](C(O)=O)=[N:53][CH:54]=1)#[N:48]>>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:11][C:12](=[O:38])[C@H:13]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19]([C:52]1[CH:51]=[CH:50][C:49]([C:47]#[N:48])=[CH:54][N:53]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)NCCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)nc1

Procedure:
N-[3-[(Benzyloxy)carbonyl]-N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester was deprotected and coupled with 5-cyano-2-pyridinecarboxylic acid to give N-[3-[(benzyloxy)carbonyl]-N-[N-[(5-cyano-2-pyridyl)carbonyl]-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 157°-158° C.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22].C(N(CC)CC)C>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:4]2[C:5]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[N:6][C:2]([C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])=[N:3]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2nc(Br)nc2N2CCCC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#C[Si](C)(C)C)nc2N2CCCC2)cc1
Temperature: 75 °C
Yield: 45.9 %

Procedure:
A mixture of 3-bromo-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (197 mg, 584 μmol, Eq: 1.00), ethynyltrimethylsilane (115 mg, 164 μl, 1.17 mmol, Eq: 2) and triethylamine (88.7 mg, 122 μl, 876 μmol, Eq: 1.5) in tetrahydrofuran (3 ml) was purged for 5 minutes with nitrogen. Then copper (I) iodide (1.11 mg, 5.84 μmol, Eq: 0.01), bis(triphenylphosphine) palladium(II) chloride (4.1 mg, 5.84 μmol, Eq: 0.01) and triphenylphosphine (1.53 mg, 5.84 μmol, Eq: 0.01) were added, the vessel was capped and heated to 75° C. for 18 hours. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 10-30% as eluent affording 1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-3-trimethylsilanylethynyl-1H-[1,2,4]triazole (95 mg/45.9%) as an orange oil. MS: m/e=355.4 (M+H+)
Reaction SMILES: [CH:1]1([C:6]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]2[CH2:31][C:30]([CH3:33])([CH3:32])[C:10]3[CH:11]=[C:12]4[C:20](=[CH:21][C:9]=3[C:8]2([CH3:35])[CH3:34])[CH2:19][C:18]2[CH:17]=[C:16]3[C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:15]3=[CH:14][C:13]4=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.[Li]CCCC.Cl[Si:60]([CH3:63])([CH3:62])[CH3:61]>C1COCC1>[CH3:61][Si:60]([CH3:63])([CH3:62])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:7]2[CH2:31][C:30]([CH3:32])([CH3:33])[C:10]3[CH:11]=[C:12]4[C:20](=[CH:21][C:9]=3[C:8]2([CH3:34])[CH3:35])[CH2:19][C:18]2[CH:17]=[C:16]3[C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25]([CH3:27])([CH3:26])[C:15]3=[CH:14][C:13]4=2)[CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC=C1)C2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)Cc1cc2c(cc1-3)C(C)(C)CC(C(c1ccccc1)(c1ccccc1)C1C=CC([Si](C)(C)C)=C1)C2(C)C
Yield: 60.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.92 g (1.48 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(1,1,4,4,7,7,10,10-octamethyl-1,2,3,4,7,8,9,10-octahydrodibenzo(b,h)-fluorenyl)diphenylmethane was placed at room temperature. Then, 20 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (light orangy brown solution). To the solution, 1.0 ml (1.63 mmol, 1.10 eq) of a hexane solution of n-BuLi was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 18 hours (dark red solution). The solution was cooled with an ice bath, and to the solution, 1.05 ml (8.28 mmol, 5.59 eq) of chlorotrimethylsilane was dropwise added by a syringe (dark brown solution). The ice bath was removed, and the solution was stirred at room temperature for 3 hours. The resulting dark brown solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. After the soluble component was extracted with 30 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellowish brown amorphous product. The amorphous product was purified by silica gel column chromatography (developing solvent: hexane:dichloromethane=19:1) to obtain 0.62 g a light yellow amorphous product (yield: 61%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH2:25])=[O:24]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[C:23]([NH2:25])=[O:24])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1CCCN1
Product: NC(=O)[C@@H]1CCCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 40 mg, 171 μmol) and (2S)-2-pyrrolidinecarboxamide (CAN 7531-52-4; 21.5 mg, 189 μmol) as starting materials and isolated (49 mg, 87%) as white solid; LC-MS (UV peak area, ESI) 100%, 330.1818 [MH+].
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([OH:24])(=[O:23])[CH3:22].OO.C(OC(=O)C)(=O)C>O>[C:21]([O:24][CH:9]1[C:10]2[N:1]=[C:2]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:23])[CH3:22]
Reactant: CCOC(=O)c1cc2c(nc1C(=O)OCC)CCCC2
Reactant: CC(=O)O
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2c(nc1C(=O)OCC)C(OC(C)=O)CCC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture comprising 2.8 g of diethyl 5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate, 10 ml of acetic acid and 1.1 ml of a 35% hydrogen peroxide aqueous solution, was stirred at 75° C. for 3 hours under heating. 1.0 ml of a 35% hydrogen peroxide aqueous solution was added thereto, and the mixture was further reacted at 75° C. for 9 hours. After cooling the mixture, water was added thereto, and the mixture was extracted with chloroform. The organic layer was dried, and then the solvent was distilled off to obtain an oily substance. This oily substance was added to 50 ml of acetic anhydride under reflux, and refluxed for 15 minutes. The solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The organic layer was dried, and then the solvent was distilled off. The residue was purified by column chromatography to obtain 2.3 g (yield: 69%) of diethyl 8-acetoxy-5,6,7,8-tetrahydroquinoline-2,3-dicarboxylate.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[CH3:8][C:9]([CH3:16])([CH3:15])[C:10](=O)[CH2:11][C:12]#[N:13].[OH-].[Na+]>O>[C:9]([C:10]1[CH:11]=[C:12]([NH2:13])[O:7][N:6]=1)([CH3:16])([CH3:15])[CH3:8]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)on1
Temperature: 25 °C

Procedure:
Hydroxylamine sulfate (27.575 g, 0.168 mol) is added to a stirred solution of 4,4-dimethyl-3-oxopentanenitrile (20 g; 0.160 mol) and sodium hydroxide (26.24 g; 0.656 mol) in water (160 mL). The mixture is heated at reflux for 2 hours, then allowed to cool to room temperature and extracted with methylene chloride. The combined organics are washed with water, dried (Na2SO4), filtered and concentrated in vacuo to afford title compound as a white solid. ESI m/z 141 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38].O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:35][CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)(O)CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)OC(C)(C)C)sc3c2)cc1
Yield: 83.1 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester (intermediate 15) (300 mg, 0.707 mmol), cesium carbonate (230 mg, 0.707 mmol) and 1-amino-2-methylpropan-2-ol (126 mg, 1.414 mmol) in 5 ml of dimethyl sulfoxide is stirred at 80° C. for 72 hours. Water is added to the reaction medium, and the mixture is extracted 3 times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution and then dried over magnesium sulfate and finally evaporated to dryness to give 290 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester in a yield of 83%.
Reaction SMILES: C([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[CH2:10][C:9](=O)[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:50]>C1COCC1.C1(C)C=CC=CC=1>[Cl:47][C:44]1[CH:45]=[C:46]2[NH:4][C:5](=[O:48])[C:6]3([CH:11]([C:12]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=4[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[O:22])[CH2:10][C:9](=[S:50])[NH:8][CH:7]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:41]2=[CH:42][CH:43]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-1-acetyl-6-chloro-2′-(5-chloro-2-methyl-phenyl)-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.04 mmol) and P2S5 (26 mg, 0.12 mmol) in THF (2 mL) was stirred at room temperature overnight, then diluted with toluene (10 mL). The resultant mixture was concentrated and washed with DCM for two times. The DCM solution was collected and purified by flash column chromtography. The product was then stirred with K2CO3 (20 mg) in MeOH for 15 min, and then partitioned between ethyl acetate and diluted HCl solution. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title product as white solid (25 mg).
Reaction SMILES: C(N(CC)CC)C.O[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1.C(Cl)[Cl:19]>>[Cl:19][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(Cl)nc1
Yield: 58.1 %

Procedure:
This example proceeded as in Example 1, but with use of 500 g of CH2Cl2 and 0.3 mole of triethylamine. The yield of 13.9 g of product mixture (content of nicotinic derivatives was 98.5 percent; the ratio of ClNS/HNS was 64/36) corresponded to a yield of 58.1 percent of 6-chloronicotinic acid and 32.7 percent of 6-hydroxynicotinic acid, related to the amount of isocinchomeronic acid-N-oxide used.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[N:16]1([CH2:1][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-formylpiperidine-1-carboxylate (110 mg, 0.51 mmol) and piperidine (53 mg, 0.62 mmol) was added NaBH(OAc)3 (153 mg, 0.73 mmol) and AcOH (37.2 mg, 35 μL, 0.62 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethylacetate. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the crude product was used directly in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([CH:14]=[O:15])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Cl
Yield: 87.8 %

Procedure:
A mixture of 7-chloro-2-iodo-thieno[3,2-b]pyridine-6-carbonitrile (1.00 g, 3.12 mmol), 4-formylphenylboronic acid (936 mg, 6.24 mmol) and 108 mgs of tetrakis(triphenylphosphine)palladium (0) in 30 mL of ethylene glycol dimethyl ether and 25 mL of aqueous saturated sodium bicarbonate is heated at reflux for 4 hours. The mixture is cooled and the precipitate is collected by filtration washing with ethyl acetate and diethyl ether to provide 818 mg of 7-chloro-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 300–305° C.; 1H NMR (CDCl3) δ 7.93 (d, J=8 Hz, 2H), 7.96 (s, 1H), 8.03 (d, J=8 Hz, 2H), 8.87 (s, 1H), 10.1 (s, 1H), MS 298.0, 300.0 (M−H)−H.