Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([OH:11])[CH2:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:18]#[N:19].[Na+]>CS(C)=O>[C:1]1([C:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)([OH:11])[CH2:8][CH2:9][C:18]#[N:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: OC(CCCl)(c1ccccc1)C1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCC(O)(c1ccccc1)C1CCCCC1
Temperature: 140 °C
Yield: 78.8 %

Procedure:
A mixture of 1-phenyl-1-cyclohexyl-3-chloro-1-propanol (3.8 g) and sodium cyanide (0.69 g) in 11 ml of dimethyl sulphoxide (DMSO) was heated at 140° C. for 3 hours. The mixture was poured into ice, then the water was extracted with ether. The solvent was removed and the residue triturated with diisopropylic ether to afford 2.7 g of 1-phenyl-1-cyclohexyl-3-cyano-1-propanol. M.p. 97°-101° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:5])=[CH:22][C:10]=2[CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccccc3)ccc2o1

Procedure:
The product from Example 71E and phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.15 (d, 3H), 1.45 (m, 1H), 1.80 (m, 2H), 2.00 (m, 1H), 2.30 (m, 1H), 2.50 (m, 2H), 3.30 (m, 4H), 6.63 (s, 1H), 7.55 (m, 314), 7.65 (m, 1H), 7.80 (m, 3H), 7.98 (d, 1H); MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:31][N:32]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: O=C1CCc2sccc21
Reactant: COc1cccc(N=C=S)c1
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc(Nc2n[nH]c3c2Cc2sccc2-3)c1
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-3-methoxy-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 in L) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-methoxy-phenyl)-amine as brown solid in 33% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:11].[K+].[OH-:16].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cccc(Cl)c1
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: OCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-chloro-3-vinyl-benzene (1.0 g, 7.2 mmol) and potassium permanganate (1.14 g, 7.2 mmol) in methanol was added 1N sodium hydroxide. The reaction mixture was stirred at room temperature for 1.5 hours. Filtered, extracted with dichloromethane, washed with sodium bicarbonate, brine, dried. Purification by silica gel chromatography (5% methanol in dichloromethane) yielded 250.0 mg of 1-(3-chlorophenyl)ethane-1,2-diol.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:11]2[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl>CN(C)C=O>[C:29]1([S:35]([NH:38][C:26]([C:23]2[CH:24]=[CH:25][C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=4[Cl:21])[C:11]=3[CH:22]=2)=[O:27])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc2nc(Cc3ccccc3)n(Cc3ccc(Cl)cc3Cl)c2c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc2nc(Cc3ccccc3)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
N,N'-carbonyldiimidazole (0.248 g) was added at a time to a solution of 0.315 g of 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole in 5 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.240 g of benzenesulfonamide and 0.233 g of diazabicycloundecene in 4 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at 100° C. for 62 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being mixed until the aqueous layer was acidified. The solution was extracted twice with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and a part of the solvent was distilled off under reduced pressure. To the residue were added 4 ml of methanol and 4 ml of a 20% potassium hydrogencarbonate aqueous solution to form a uniform solution. This solution was then adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 0.310 g of 6-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole (244).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=[O:14])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].CC(=CC)C.Cl([O-])=[O:40].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=4)[CH2:12][C:13]([OH:40])=[O:14])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CS(=O)(=O)c1cc([C@H](CC(=O)O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 8 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (0.10 g, 0.21 mmol) and 2-methyl-2-butene (147 μL, 1.39 mmol) in t-butanol (1 mL) was added a solution of 80% sodium chlorite (31 mg, 0.28 mmol) and sodium dihydrogen phosphate monohydrate (38 mg, 0.28 mmol) in water (400 μL) (addition was exothermic). The mixture stirred overnight and was then concentrated in vacuo, acidified with 1 N aqueous HCl (pH=2), diluted with brine (25 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid which was used without further purification.
Reaction SMILES: [C:1]([OH:8])(=O)[C:2]#[C:3][CH2:4][CH2:5][CH3:6].[CH:9]1([NH2:12])[CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl>ClCCl>[CH:9]1([NH:12][C:1](=[O:8])[C:2]#[C:3][CH2:4][CH2:5][CH3:6])[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: CCCC#CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCC#CC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 2-hexynoic acid (5.03 g) and cyclopropylamine (2.70 g) in dichloromethane (75 ml), and a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.00 g) and 1-hydroxybenzotriazole hydrate (7.19 g) in dichloromethane (75 ml) were mixed, and the mixture was stirred at room temperature for 18 hr. 1N Hydrochloric acid (200 ml) was added, and the mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column to give the title compound (6.04 g, 89%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(N2CCNCC2)n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A solution of 2-chloro-6-(trifluoromethyl)pyridine (1.0 g, 5.5 mmol), piperazine (1.4 g, 16.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) were mixed in DMF (10 mL) in a sealed tube. The mixture was heated at 100° C. overnight. The reaction mixture was concentrated and chromatographed on silica gel (ethyl acetate to EA/MeOH/Et3N=9:1:0.5) to give 1.05 g of the desired product. MS calculated for C10H12F3N3: (M+H) 232.1; found 232.1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=2)=[CH:32][CH:31]=1>C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=2[C:7]([C:6]2[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:9])=[CH:32][CH:31]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C(C)C
Yield: 77.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.03 g, 4.35 mmol, RN-117439-59-5), oxalyl chloride (0.417 mL, 4.79 mmol), N,N-dimethylformaride (2 drops), tin (IV) chloride (0.560 mL, 4.79 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.35 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.63 g (77%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ 1.16 (d, 12 H), 1.80 (s, 3 H), 2.19 (s, 3 H), 3.28 (septet, 2 H), 3.74 (s, 3 H), 3.83 (s, 2 H), 6.98 (d, 2 H), 7.41 (dd, 2 H), 7.44 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:32][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: COc1ccc(CCN)cc1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(NCCc2ccc(OC)cc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
To a mixture of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester [1 g, 4.83 mmol, Intermediate (54)] and N,N-diisopropylethylamine (1.27 mL, 7.25 mmol) in THF (16 mL) is added 2-(4-methoxyphenyl)-ethylamine (707 μL, 4.83 mmol). The resulting mixture is stirred at ambient temperature for 20 hours and poured into 50 mL water and extracted three times with 40 mL ethyl acetate. The organic extracts are combined and washed with 20 mL brine, dried over magnesium sulfate, filtered and concentrated to afford a solid which is purified via flash column chromatography on silica gel (35 g) eluting with 5 to 50% EtOAc in heptane gradient to afford 2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid methyl ester [1 g, 64.5%, Intermediate (55)]. LCMS: RT=2.9 minutes, MS: 322 (M+H).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][CH2:17][C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:20][C@H:21](O)[CH3:22].C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:31]([C@@H:21]([CH3:22])[CH2:20][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([CH2:17][CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C2C=c3c(cnn3C[C@@H](C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 91.1 %

Procedure:
0.85 ml (10.7 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.3 g (5.3 mmol) of (R)-1-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.05 ml (21.4 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.83 g (12.5 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.3 g (90%) of (S)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[OH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[OH-].[K+].Cl>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:21]1[CH:22]=[CH:23][C:18](=[O:17])[CH:19]=[CH:20]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Reactant: Oc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
First, 9.007 g of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 7.611 g of 4-hydroxypyridine, and 5.219 g of powdered potassium hydroxide were added to 120 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 2 hours in a nitrogen atmosphere. Then, 50 ml of ice water and 30 ml of 4N hydrochloric acid were added to the reaction mixture so as to make it weakly acidic (pH 3 to 4). The resultant yellow precipitate was filtered and washed with water. The precipitate was dissolved by heating in a mixture containing 560 ml of water and 56 ml of conc. aqueous ammonia. One gram of activated carbon was added to the resultant mixture, stirred, and filtered. The filtrate was neutralized with conc. hydrochloric acid and ice-cooled. The precipitated crystals were then filtered and washed with water, methanol, and ethanol, successively. The resultant crystals were dried to give 7.56 g of 6-nitro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione (hereinafter, abbreviated as Ia).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:12][CH:13]([C:15]#[N:16])[CH2:14]1)=[O:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (47 mg, 0.185 mmol) was dissolved in dichloromethane (1 ml) and cooled in an ice bath. Trifluoroacetic acid (0.5 ml) was slowly added and the reaction was stirred at room temperature for 2 h then evaporated and dried under high vacuum to afford 1-((R)-2-amino-propionyl)-azetidine-3-carbonitrile trifluoroacetate which was used without further purification.
Reaction SMILES: [H][H].NC1C=C(N)C=CC=1C.NC1C=CC=C(N)C=1C.[N+:21]([C:24]1[CH:29]=[C:28]([N+]([O-])=O)[CH:27]=[CH:26][C:25]=1[CH3:33])([O-:23])=[O:22].[N+:34](C1C=CC=C([N+]([O-])=O)C=1C)([O-:36])=[O:35]>O>[N+:34]([C:29]1[C:24]([N+:21]([O-:23])=[O:22])=[C:25]([CH3:33])[CH:26]=[CH:27][CH:28]=1)([O-:36])=[O:35]
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cc1c(N)cccc1N
Agent: Cc1ccc(N)cc1N
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
An autoclave having a volume of 1000 ml and equipped with a gassing stirrer, a hydrogen supply pipe, an inlet pipe for the nitro compound and an outlet valve for excess hydrogen was used. The reaction mixture left the reactor through a frit, which retained the catalyst. The temperature in the reactor was regulated by means of an external heating or cooling circuit. A coiled cooling pipe inside the reactor provided additional cooling of the reaction mixture. 480 g of a commercial mixture comprising a mixture of 80% 2,4-diaminotoluene and 20% 2,6-diaminotoluene (TDA) with water in a weight ratio of TDA to water of 63:37 as well as 5.0 g-6.5 g of catalyst were placed in the reactor. The contents of the reactor were then placed under pressure by means of hydrogen and heated. At a temperature of 180° C. and a pressure of 26 bar, 125 g/h of a commercial mixture of 80% 2,4-dinitrotoluene and 20% 2,6-dinitrotoluene were passed into the reactor hourly and hydrogenation was carried out until the catalyst was exhausted. The resulting hydrogenation product was removed from the reactor continuously and worked up to form the pure diaminotoluene isomeric mixture.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. p-Toluenesulfonyl chloride (available from Sigma-Aldrich; 103 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 12% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (76 mg, 46%) as a white solid. MS cald. for C24H25FNO4S [(M+H)+]: 456, obsd. 456.4.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC1C=CC=CC=1C.ClCCl.CO>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:23][N:24]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cnc(-c2ccccc2)nc1
Reactant: NNC(=O)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Solvent: CO
Product: c1ccc(-c2ncc(-c3nnc(-c4ccccc4)[nH]3)cn2)cc1
Temperature: 200 °C
Reaction time: 24 h
Yield: 6.1 %

Procedure:
2-Phenyl-pyrimidine-5-carbonitrile (Biofine International, 0.10 g, 0.55 mmol) and benzoic hydrazide (Aldrich, 0.075 g, 0.55 mmol) were dissolved in o-xylene (5 mL) and heated to 200° C. in a sealed pressure tube while stirring for 24 hours. After cooling to room temperature, the reaction mixture was heated to 200° C. in an open vessel under a stream of nitrogen for six hours. The remaining crude solid was dissolved in a minimal amount of 98:2 v/v dichloromethane-methanol and purified by flash silica column chromatography. Elution through a 40-g Analogix® flash silica cartridge with 100% dichloromethane to 2% methanol in dichloromethane afforded the title compound as a pale yellow solid (10 mg, 6% yield); Rf 0.1 with 98:2 v/v dichloromethane-methanol; melting point 280-282° C.; 1H-NMR (400 MHz; CDCl3) δ 8.48-8.42 (m, 2H), 8.12-8.06 (m, 2H), 7.60-7.48 (m, 6H); MS (ESI+) m/z 300.1 (M+1); H-PGDS FPBA IC50: 1.0 μM; H-PGDS inhibitor EIA IC50: 0.084 μM.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[C:3]=1[OH:10]
Reactant: C=C[Mg]Cl
Reactant: O=Cc1cccc(F)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(F)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
After a solution of 3-fluoro-2-hydroxybenzaldehyde (600 mg, 4.28 mmol) in THF (10 ml) was cooled to 0° C., a solution of vinyl magnesium chloride in THF (1.9M, 5.42 ml, 10.3 mmol) was added thereto over 5 minutes. The mixture was gradually warmed to room temperature and stirred at room temperature overnight. The mixture was cooled to 0° C. and a saturated aqueous ammonium chloride solution was added thereto at 0° C. The mixture was extracted with ethyl acetate. The organic layer was combined and successively washed with water and a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated to obtain 772 mg of 2-fluoro-6-(1-hydroxy-2-propenyl)phenol as a pale yellow oil.