Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:38].[OH-]>O>[C:1]1([C:7](=[C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([NH2:38])=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(OCC(=O)O)cc2)CC(C)(C)C1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(OCC(N)=O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
To a solution of 34 (100 mg, 0.26 mmol) and CH2Cl2 (mL) was added oxalyl chloride (90 uL, 1.06 mmol) and the mixture was stirred at RT for 2 h. To this solution 10 mL of NH4OH (30% aqueous) was slowly introduced and stirred for 6 h. The mixture was poured into H2O (100 mL) and then extracted with EtOAc (2×100 mL). The organic layer was worked-out to give the crude product, which upon purification gave 11 mg (11%) of the desired product 35 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.48 (br s, 1H), 7.35 (br s, 1H), 7.27 (app. J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.2 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 1.91 (s, 2H), 1.87 (s, 2H), 1.25 (s, 2H), 0.88 (s, 6H), 0.87 (s, 6H). LCMS (ESI): m/z 378 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:17])[N:10]2[CH2:13][C@H:14]2[CH2:16][O:15]2)=[CH:5][CH:4]=1.[N+](C1C=C(S(OC[C@H]2CO2)(=O)=O)C=CC=1)([O-])=O.[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>CN(C=O)C>[OH:15][C@@H:14]([CH2:13][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:12]=2)[CH2:7][CH2:8][C:9]1=[O:17])[CH2:16][N:35]1[CH2:36][CH2:37][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:39][CH2:40]1
Reactant: COc1ccc2c(n1)N(C[C@H]1CO1)C(=O)CC2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N(C[C@H](O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Temperature: 110 °C

Procedure:
A mixture of 7-(methyloxy)-1-[(2S)-2-oxiranylmethyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one (made according to the general method of Example 5(f) but using (2R)-2-oxiranylmethyl 3-nitrobenzenesulfonate) (3.1 g, 13.3 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (2.7 g, 13.3 mmol) in DMF (3 ml) was heated at 110° C. for 1 h. DMF was then evaporated. The crude product was purified by silica chromatography using a 0-10% methanol/dichlormethane gradient to provide the desired compound as a pale yellow solid, presumed R enantiomer (3.9 g; 89%; 90% purity).
Reaction SMILES: [Na+].[P:2]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[C@H:14]([OH:27])[C@@H:13]1[OH:28])([O:5][P:6]([O-:9])([O-:8])=[O:7])(=[O:4])[O-:3].[Na+].[Na+].N1C=CC=CC=1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>ClCCl>[P:2]([O:10][CH2:11][C@H:12]1[O:16][C@@:15]([Si:38]([CH3:40])([CH3:39])[CH3:37])([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[C@H:14]([OH:27])[C@@H:13]1[OH:28])([O:5][P:6]([OH:8])([OH:9])=[O:7])(=[O:3])[OH:4]
Reactant: C[Si](C)(C)Cl
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)([O-])OP(=O)([O-])[O-])[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)[C@@]1(n2cnc3c(N)ncnc32)O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a 500 mL round-bottomed flask was added 3 g (21.7 mmol) adenosine-5′-diphosphate sodium salt and 200 mL pyridine. After the salt had dissolved. the solution was cooled to 0° C. under nitrogen atmosphere. Trimethylsilyl chloride (85 g, 800 mmol) in 200 mL dichloromethane was added slowly to the solution. After this addition was complete, the reaction was stirred at 35° C. for 8 hr. The pyridine hydrochloride salt was removed by filtration and excess pyridine and dichloromethane removed under high vacuum for 24 hr to yield 19.3 g (21.3 mmol) of TMS-ADP. The product was used without further purification. This synthesis is illustrated in FIG. 4E.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[N+]=[N-])=[CH:35][CH:34]=1)=[NH:32])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C(Br)C1C=CC=CC=1)#N>C1COCC1>[NH2:38][CH2:37][C:36]1[CH:41]=[CH:42][C:33]([C:31](=[NH:32])[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:34][CH:35]=1
Reactant: [N-]=[N+]=NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Agent: N#CC(Br)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1

Procedure:
26.3 g (100 mmol) triphenylphosphine was added at room temperature to the 4-(benzyloxycarbonylamidino) benzyl azide from (iii) above dissolved in 160 ml THF. After 16 h an additional 6.6 g (25 mmol) triphenylphosphine was added and the solution was allowed to stand for 4 h before removal of the solvent in vacuo. The residue was dissolved in methylene Chloride and extracted with 2M HCl. The aqueous phase was washed with methylene chloride and ether and was subsequently made alcaline with 3.75M sodium hydroxide solution. Extraction with methylene chloride followed by drying (K2CO3) and removal of the solvent in vacuo gave 20 g (The total yield starting from cyanobenzyl bromide is 28%) of a yellow oil which solidified on standing.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[O:14]=[C:4]1[C:5]2[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][CH:2]=[CH:3]1
Reactant: CCOC(=O)CBr
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: CCOC(=O)Cn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with ethyl bromoacetate to give 6.0 g of product, mp 163°-165° C, after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)s1

Procedure:
480 mg (2.95 mmol) of 5-chlorothiophene-2-carboxylic acid are dissolved in 24 ml of dichloromethane, and 2.4 ml (27.5 mmol) of oxalyl chloride are added. The mixture is heated under reflux for 16 h. It is then concentrated in vacuo, and the residue is again mixed with dichloromethane and concentrated once again. A viscous oil remains and is dried under high vacuum. 534 mg (quant.) of the target compound are obtained and are reacted further without further purification and characterization.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CNCCN1
Reactant: Brc1ccc(C2CCCCC2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: c1cc(N2CCNCC2)ccc1C1CCCCC1

Procedure:
A target compound (2.01 g, 8.224 mmol, 45.7%) was yielded in the same manner as Reference Example 10 by reacting 1-bromo-4-cyclohexylbenzene (3.34 mL, 18 mmol) with piperazine (2.01 g, 23.4 mmol), sodium t-butoxide (2.51 g, 26.1 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (424.4 mg, 0.54 mmol) and purifying by separation through column chromatography (CH2Cl2/MeOH, 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]([C:23](=O)[C:24]([F:27])([F:26])[F:25])=[CH:19][N:20](C)C)[O:11][N:10]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:40]([C:41]([O:43][CH3:44])=[O:42])=[C:39]([NH:45]N)[O:38][N:37]=2)=[CH:32][CH:31]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:45]([C:39]3[O:38][N:37]=[C:36]([C:33]4[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][CH:34]=4)[C:40]=3[C:41]([O:43][CH3:44])=[O:42])[C:23]=2[C:24]([F:25])([F:26])[F:27])[O:11][N:10]=1
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C(=CN(C)C)C(=O)C(F)(F)F
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)noc1NN
Solvent: CCO
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2onc(-c3ccc(Cl)cc3)c2C(=O)OC)c1C(F)(F)F
Temperature: 60 °C
Yield: 37.2 %

Procedure:
The mixture of methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(dimethylamino)-4,4,4-trifluoro-3-oxobut-1-en-2-yl)isoxazole-4-carboxylate (157 mg, 0.37 mmol) and methyl 3-(4-chlorophenyl)-5-hydrazinoisoxazole-4-carboxylate (0.1 g, 0.37 mmol) in ethanol (1 mL) was heated at 60° C. for 5 h, the solution was evaporated and the product was crystallized from methanol to give 86 mg (37%) of example 131. 1H NMR (DMSO-D6, CCl4): 3.69 (3H, s, OCH3), 3.71 (3H, s, OCH3), 7.35 (1H, dd, CH-arom.), 7.47 (1H, d, CH-arom.), 7.57 (2H, AB-syst., CH-arom.), 7.63 (1H, m, CH-arom.), 7.84 (2H, AB-syst., CH-arom.), 8.74 (1H, s, CH pyrazol.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)[C:5]([F:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([F:39])=[CH:25][C:26]([CH:36]2[CH2:38][CH2:37]2)=[C:27]([N:29]2[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]2)[CH:28]=1>C(O)(C(F)(F)F)=O.C(O)(C)C>[F:21][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([C:13](=[O:18])[CH2:14][CH2:15]3)[C:11]([CH3:20])([CH3:19])[CH2:10]2)=[N:7][C:2]([NH:22][C:23]2[C:24]([F:39])=[CH:25][C:26]([CH:36]3[CH2:38][CH2:37]3)=[C:27]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:28]=2)=[N:3][CH:4]=1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2C2CC2)c1=O
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC2CCC(=O)N21
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(NC4CC5CCC(=O)N5C(C)(C)C4)n3)c(F)cc2C2CC2)c1=O
Temperature: 100 °C

Procedure:
A mixture of 7-(2-chloro-5-fluoropyrimidin-4-ylamino)-hexahydro-5,5-dimethylindolizin-3(5H)-one isomer A (cis) (50 mg), 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (50 mg) and TFA (5 drops) in isopropanol (1 ml) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed in vacuo and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give product as racemic mixture.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSc1ccc(N)cc1
Solvent: c1ccncc1
Product: CSc1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dissolve 4-(methylmercapto) aniline (1.39 g, 10 mmol) in anhydrous pyridine (25 mL) and cool to 5° C. Add, by dropwise addition, p-toluenesulfonyl chloride (2.1 g, 11 mmol) and stir overnight. Partition between water and ethyl acetate and separate the organic phase. Wash the organic phase with cold 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH2:1](N(CC)CCN)C.C(N([CH2:14][CH2:15][NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]1[C:21]([N+:26]([O-:28])=[O:27])=[N:22][N:23]([CH3:25])[CH:24]=1)CC)C>>[CH:15]1([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[C:21]([N+:26]([O-:28])=[O:27])=[N:22][N:23]([CH3:25])[CH:24]=2)[CH2:14][CH2:1]1
Reactant: CCN(CC)CCN
Reactant: CCN(CC)CCNC(=O)C=Cc1cn(C)nc1[N+](=O)[O-]
Product: Cn1cc(C=CC(=O)NC2CC2)c([N+](=O)[O-])n1

Procedure:
N,N-diethylethylenediamine, 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid N-diethylaminoethylamide; m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=O)[CH3:18].C(N(CC)CC)C>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:13][C:14]([OH:16])=[O:15])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(CC(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.7 %

Procedure:
A solution of 3-(4-chlorophenyl)glutaric acid (1.0 g, 4.1 mmol) in acetic anhydride (20 mL, 200 mmol) was heated to reflux, stirred for 17 h, cooled at room temperature, and concentrated to dryness. The crude residue was dried under vacuum for 1 h. The crude anhydride was dissolved in ethanol (30 mL) and triethylamine (3.0 mL, 22 mmol) was added. The reaction was stirred for 17 h at room temperature and then concentrated to dryness. The crude residue was dissolved in dichloromethane (5 mL) and purified on SiO2 (40 g) using 5% MeOH/DCM to provide the title product (0.785 g, 70% yield) as a clear oil. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 12.09 (s, 1H), 7.30-7.22 (m, 4H), 3.93-3.87 (m, 2H), 3.4 (m, 1H), 2.71-2.46 (s, 4H), 1.0 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.CCN(C(C)C)C(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:7]2[CH:6]=[C:5]([Cl:9])[N:4]=[N:3][C:2]=2[Cl:1])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2Cl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
3,4,6-Trichloropyridazin (10.5 g; 57.25 mmol) was dissolved in 10 ml of dry NMP. Afterwards were added DIPEA (28.4 ml; 171.73 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (12.04 g; 60.11 mmol) and all let stir at ambient temperature for 16 hours and 3 hours at 50° C. The reaction mixture was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1ccccn1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1ccccn1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-pyridinecarboxaldehyde (0.5 g, 4.7 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.071 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1C(=O)C(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 6-bromoisatin (CAS#6326-79-0, 4.52 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mind). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered and concentrated to provide 6-bromo-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 6-bromo-1-methyl-1H-indole-2,3-dione (1.0 g, 4.2 mmol) was then treated with hydrazine hydrate (7.0 mL, 225 mmol). The reaction was heated to 130° C. and stirred for 80 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 6-bromo-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 225.9 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[CH3:13])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[CH3:13]
Reactant: CC(=O)Oc1ccc(C#N)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C#N)ccc1O
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A stirred solution of 4-cyano-2-methylphenyl acetate (5.2 g, 29.7 mmol) in 75 mL of methanol was treated with a solution of potassium carbonate (30 mmol, 4.15 g) in 25 mL of water at room temperature. After 30 minutes, the mixture was concentrated in vacuo and treated with 1 N sulfuric acid. The resulting precipitate was filtered, washed with water, and dried to give 3.1 g of 4-hydroxy-3-methylbenzonitrile as a white solid (78% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]([N:20]2[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: OC1CCNCC1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Yield: 67.2 %

Procedure:
A solution of 5 g of 5-chloro-2-nitrobenzaldehyde dimethylacetal and 8.8 g of 4-hydroxypiperidine in 20 ml of N,N-dimethylformamide was heated at 80 ° C. for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated under a reduced pressure. The residue was purified by a silica gel column chromatography to give 4.3 g of 5-(4-hydroxypiperidino)-2-nitrobenzaldehyde dimethylacetal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[H-].[Na+].[Cl:31]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:31][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
Under an argon atmosphere, to a mixture of ethyl 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.32 g) in DMF (11 mL) was added sodium hydride (60%, 0.14 g) at 0° C., and the mixture was stirred at room temperature for 30 min. N-Chlorosuccinimide (0.46 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (0.15 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(Cl)(Cl)Cl.[CH3:23][O:24][C:25]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([NH:12][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:25]=3[O:24][CH3:23])=[CH:9][CH:10]=2)[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc3c(c2[N+](=O)[O-])C(=O)NC(=O)C3(C)C)c(OC)c1

Procedure:
2.7 gm of 4,4-dimethyl-7-amino-8-nitro-2H,4H-isoquinoline-1,3-dione were admixed with 50 ml of chloroform and 2.5 ml of triethylamine. Subsequently, 2.2 gm of 2,4-dimethoxybenzoylchloride were added, and the mixture was refluxed for 2 hours. After cooling the solution was evaporated and the precipitate was suction-filtered off and digested with water while heating.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[O:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: Nc1c(F)cc(-c2ccc3c(c2)OCO3)cc1Cl
Yield: 60.5 %

Procedure:
The title compound (143 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (200 mg, 0.89 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (192 mg, 1.16 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.36-7.30 (m, 2H), 7.20 (d, J 1.7, 1H), 7.06 (dd, J 1.4, 8.1, 1H), 6.91 (d, J 8.1, 1H), 6.01 (s, 2H), 5.42 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3C=C4[C:24](=[C:25]([C:31](OC)=[O:32])[C:26]=3[CH2:27][CH2:28][C:29]#[N:30])C35OCOC3C=CC=C5C=C4)=[CH:9][C:4]=2[O:3][CH2:2]1.CN([CH:38]=[O:39])C>[Ni]>[NH2:30][CH2:29][CH2:28][CH2:27][C:26]1[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[C:6]2[C:7]([CH:8]=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=32)=[CH:24][C:25]=1[C:31]([O:39][CH3:38])=[O:32]
Reactant: COC(=O)c1c(CCC#N)c(-c2ccc3c(c2)OCO3)cc2c1C13OCOC1C=CC=C3C=C2
Reactant: CN(C)C=O
Agent: [Ni]
Product: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CCCN)OCO3
Reaction time: 6 h

Procedure:
To a DMF (1 ml) solution of methyl 9-(1,3-benzodioxol-5-yl)-8-(2-cyanoethyl)-naphtho[1,2-d]-1,3-benzodioxole-7-carboxylate (21 mg) was added Raney nickel (about 200 mg) and stirred for 6 hours under hydrogen atmosphere. The catalist was filtered off and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified with column chromatography (silica gel 1 g, eluent:dichloromethane-methanol concentrated NH4OH=15:1:0.1) to give the entitled compound (11 mg).