Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.BrC1C=CC(Cl)=NC=1.O>CS(C)=O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:23][CH:24]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Clc1ccc(Br)cn1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 0.25 h
Yield: 68 %

Procedure:
N-Boc-L-Tyrosine (0.844 g, 3 mmol) and KOBu-t (0.727 g, 6.5 mmol) are dissolved in dry DMSO (2.9 mL) under argon atmosphere in a tightly closed glass reaction tube and stirred for 15 min, then 4-chloroquinoline (0.491 g, 3 mmol) is added. The mixture is stirred for 6 days at 30° C. When only traces of 5-bromo-2-chloropyridine are detected (LC-MS control), the reaction mixture is poured into water (40 mL) and the aqueous phase is washed with diethyl ether (2×20 mL). The pH of aqueous phase is adjusted to ˜4 by adding 20% aqueous citric acid. The product precipitated is collected on filter and washed with water (50 mL) to give the title compound (0.833 g, 68%) as a grey solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-bromophenol (10 g). To the mixture were added potassium carbonate (10.4 g) and bromopropane (6.0 ml), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-3-propoxybenzene (11.2 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[C@H:19]3[C:14]([C:15]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:16]=4[C@@H:17]([CH2:20][NH:21]5)[CH2:18]3)=[CH:13][C@@H:12]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:33].OO>CO.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[C:1]1([NH:7][C:8]([N:10]2[C@H:19]3[C:14]([C:15]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:16]=4[C:17](=[CH:20][N:21]5[OH:33])[CH2:18]3)=[CH:13][C@@H:12]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: O=C([C@@H]1C=C2c3cccc4c3[C@@H](CN4)C[C@H]2N(C(=O)Nc2ccccc2)C1)N1CCCC1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=C([C@@H]1C=C2c3cccc4c3c(cn4O)C[C@H]2N(C(=O)Nc2ccccc2)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
212 mg (0.49 mmol) of the product of step 1 is dissolved in 12 ml methanol and 41 mg (0.12 mmol, 0.25 eq.) sodium wolframate dehydrate in some drops of water is added. Then 670 μl 30% H2O2 (10 eq.) is added at 0° C. and stirred at room temperature for 50 minutes. The reaction mixture is separated with dichloromethane and saturated aqueous bicarbonate solution, the organic layer is washed with brine, dried with Na2SO4 and evaporated and purified by chromatography on silica eluting with tert. butyl methyl ether:cyclohexane 9:1 to give (6aR,9R)-4-Hydroxy-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-7-carboxylic acid phenylamide. MS/ES: 441 (M+H)+
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:29][C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:29][C:30]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)Cl)CCC3
Reaction time: 3 h
Yield: 193.6 %

Procedure:
To a solution of 3.83 g of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 40 ml of dichloromethane were added 1.3 ml of pyridine and 1.29 g of triphosgene under ice-cooling, followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and an aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. To the residue was added hexane, followed by stirring, and the solid was collected by filtration and dried to obtain 3.07 g of t-butyl 1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[BH3-]C#N.[Na+].[Cl:23][C:24]1[C:25]([CH2:34][CH:35]=O)=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[C:29]#[N:30]>C(Cl)Cl>[Cl:23][C:24]1[C:25]([CH2:34][CH2:35][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[CH:10]=3)[CH2:2][CH2:3]2)=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(CC=O)c(Cl)cc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)c(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (90 mg, 0.190 mmol) and NaBH3CN (24 mg, 0.380 mmol) in 20 mL DCM was added 5-chloro-2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.190 mmol) and the mixture was stirred at RT overnight. Concentrated, and the residue was purified by prep-TLC to give 5-chloro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, MeOD) δ ppm 7.82 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.50˜7.53 (m, 2H), 7.20 (s, 1H), 5.35 (s, 2H), 3.95 (s, 3H), 3.23˜3.26 (m, 6H), 3.10˜3.16 (m, 8H), 3.00˜3.03 (m, 2H). MS m/e 441 (M+1)+. (0.094 μM)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].OC1OC[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[C:9]1=O>C(Cl)Cl.CN(C=O)C>[Cl:4][CH:2]1[O:3][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=2)[C:1]1=[O:5]
Reactant: O=C1C(O)OCN1c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(Cl)OCN1c1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
Oxalyl chloride (2.7 ml) was added dropwise over 1 min to a stirred solution of 5-hydroxy-3-(3-trifluoromethoxyphenyl)oxazolidin-4-one (8.17 g) in DCM (60 ml) containing DMF (1 drop) at 0° C. The mixture was allowed to warm to room temperature and once gas evolution had stopped the solvent was removed in vacuo to give the sub-title compound (8.5 g) which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24]C)=[O:23])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:14][CH:13]3[CH2:15][CH:10]([CH2:11][CH2:12]3)[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([OH:24])=[O:23])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Yield: 102.3 %

Procedure:
A solution of methyl (E)-7-[3-(4-fluorophenyl)bicyclo[3.2.1]oct-2-en-2-yl]-3,5-dihydroxy-hept-6-enoate (1.30 g, 3.47 mmoles) and aqueous NaOH (5.2 ml of a 1N solution) in 15 ml methanol was stirred for 30 minutes at 25° C., cooled to 0°-5° C., acidified, diluted with water and extracted with ethyl acetate. The organic layers were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo provided 1.28 g of the solid product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(c2cc(Cl)nc3cc(-c4ccccc4)nn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
There was dissolved, in 1,4-dioxana (3 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (50.4 mg, 0.191 mM), then 1-(2-hydroxyethyl)-piperazine (46 μL, 0.382 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture and the resulting solid was washed with ethyl acetate to thus give the title compound in a quantitative yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1

Procedure:
A solution of 2300 mg (5.87 mmol) of ethyl E-6-[2-(4-cyanophenyl)ethyl]-8-(2-hydroxyphenyl)oct-7-enoate in 160 ml of dry acetonitrile is mixed with 1600 mg (7.05 mmol) of 4-(tert-butyl)benzyl bromide and 1220 mg (8.81 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulfate and the organic phase concentrated. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 2800 mg (5.21 mmol, 88% of theory) of a solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH3:22])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:23])[CH:5]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2
Temperature: 80 °C

Procedure:
A mixture containing [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (Example 20, Step D) (1.07 g, 0.003 mole), potassium carbonate (0.41 g, 0.003 mole) and benzyl bromoacetate (0.69 g, 0.003 mole) in dimethylformamide (35 ml) is heated at 80° C. for two hours. Then this mixture is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride, washed with aqueous sodium bicarbonate and then water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a viscous oil which is triturated with ether to give 1.06 g. of product.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:23]1([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1

Procedure:
A solution of 11 (0.315 g, 0.62 mmol), acetic acid (30 μL, 0.63 mmol) and tetrabutylammonium fluoride (1M in THF, 0.65 mL, 0.65 mmol) in 3 mL THF was stirred for 10 minutes under nitrogen. The solvent was removed in vacuo and the residue flash chromatographed with dichloromethane followed by 19:1 chloroform/methanol to give 0.164 g (98%) of the anomers. The anomers were separated by centrifugal chromatography with 19:1 chloroform/methanol: yield of β-anomer 10 mg; mp. 125°-128 C; [α]D25 +2.5° (c=0.1CH3OH); FAB MS 271 (M+H)+ ; 1H NMR (CDCl3) δ 9.0 (s, 1, H-2), 8.8 (s, 1, H-8), 6.3 (m, 1, 5'-OH), 3.8 (m, 1, 5'-H), 3.65 (m, 2, 4'-H, 5'-H), 2.6 (m, 1, 2'-H), 2.45 (m, 1, 2'-H), 2.2 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.ClC1C=CC(C(O)=O)=C(OC)C=1.S(Cl)(Cl)=O.Cl.Cl.[NH2:31][C:32]1[C:37]([NH2:38])=[CH:36][N:35]=[CH:34][N:33]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:31][C:32]1[C:37]([NH:38][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[O:11][CH3:12])=[CH:36][N:35]=[CH:34][N:33]=1
Reactant: Nc1cncnc1N
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: COc1cc(Cl)ccc1C(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1C(=O)Nc1cncnc1N
Reaction time: 2 h

Procedure:
The 4-chloro-2-methoxy-benzoyl chloride prepared from 5.6 g of 4-chloro-2-methoxy-benzoic acid and 100 ml of thionyl chloride was dissolved as crude product in 100 ml of pyridine and mixed successively with 5 g of 4,5-diaminopyrimidine dihydrochloride and 1 g of 4-dimethylamino pyridine. After stirring for at first 2 hours at room termperature and then for 1.5 hours at 100° C., the reaction mixture was evaporated to dryness, mixed with water, and neutralized with sodium bicarbonate. The precipitate obtained was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[C:12](=[N+:15]=[N-:16])[CH:13]=O)[CH3:9].CC(O)=O>CCO>[CH2:8]([O:10][C:11]([C:12]1[N:15]=[N:16][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:17])[CH3:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccccc2)nn1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Oxalyl chloride (4.7 g, 30.1 mL, 37.0 mmol) was added to a cold (0-4° C.) solution of DMF (2.25 g, 2.4 mL, 30.8 mmol) in CHCl3 (20 mL) and stirring was continued for 10 minutes. The reaction mixture was heated at 40° C. for 10 minutes and cooled to −10° C. Diazoacetic acid ethyl ester (3.5 g, 3.5 mL, 30.6 mmol) was then added and stirred at room temperature for 1 hr. The reaction mixture was concentrated ether was then added, the precipite was collected and dissolved in 10% aq Hac (10 mL) and stirring was continued for 1 hr. The reaction mixture was extracted with ether, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 590 mg (21% Yield) of 2-diazo-3-oxo-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 9.7 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H). Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HOAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. The reaction mixture was concentrated and cold water was then added, the solid was collected to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H). LiOH.H2O (80 mg, 1.9 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (130 mg, 0.6 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure. Cold water was then added and it was acidified with 10% aqueous HCl, the solid was collected to afford 40 mg (35.4% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.4 (bs, 1H), 9.4 (s, 1H), 8.0 (d, 2H), 7.7 (t, 2H), 7.6 (t, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:21][CH:22]([CH3:50])[CH2:23][CH:24]([CH2:27][O:28][C:29](=[O:49])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:25][OH:26])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:1][S:2]([O:26][CH2:25][CH:24]([CH2:23][CH:22]([O:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:50])[CH2:27][O:28][C:29](=[O:49])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC(C)OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COS(C)(=O)=O)CC(C)OC(=O)c1ccccc1

Procedure:
Using 0.358 ml (4.63 mM) of methanesulfonyl chloride and 0.814 ml (5.79 mM) of triethylamine, 2.059 g (3.86 mM) of 2-(2-benzoyloxypropan-1-yl)-3-octadecylcarbamoyloxypropanol m7 in dichloromethane is converted to the crude titled compound m7a by the same procedure as described in (50).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[OH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]2=[O:33])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 15 g (0.056 mol) of α,α-diphenyl-4-piperidinemethanol, 14.5 g (0.056 mol) of 2-(2-bromoethyl)-1H-isoindole-1,3-dione and 6.7 g (0.063 mol) of sodium carbonate in 150 ml of methyl isobutyl ketone is heated at reflux temperature for 5 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:15]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:16]2[C:1](=[CH:2][CH:13]=[CH:12][CH:11]=2)[O:3]1)[CH3:8]
Reactant: CCOC(=O)CN(C)C
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C2CC(CN(C)C)Oc3ccccc32)cc1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using p-bromoanisole in place of 4-bromochlorobenzene in part (c) to yield the title compound which was isolated as the hydrobromide salt.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:34]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=3[F:32])(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1F
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3F)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2,4-difluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.98-7.90 (1H, m), 7.47-7.41 (2H, m), 7.35-7.22 (7H, m), 7.07-6.92 (2H, m), 6.16 (1H, br.s), 3.50-3.43 (2H, m), 2.84 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.23 (3H, s).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)(O)[O-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCn1cncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCCn1cncn1)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a stirred mixture of 1.89 g of 1H-1,2,4-triazole-1-propanamine in 50 ml of dichloromethane containing an excess of saturated sodium bicarbonate solution was added, all at once, 3.17 g of 4-chlorobenzenesulfonyl chloride. Vigorous stirring was continued for 24 hours. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a gum.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10]Cl)[N:6]=1)[C:2]([CH3:4])=[O:3].C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: C1CCNCC1
Reactant: CC(=O)Cc1nc(CCl)no1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Cc1nc(CN2CCCCC2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.8 %

Procedure:
To a solution of 15.0 g of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole in 50 ml of THF were added dropwise 17.4 g of triethylamine and subsequently 11.0 g of piperidine. The mixture was stirred at room temperature for 24 hours and then heated under reflux for 6 hours. After cooling, the precipitated material was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (20:1, v/v) as eluent to give 10.9 g of 5-acetonyl-3-piperidinomethyl-1,2,4-oxadiazole as a colorless solid, m.p. 66°-67° C.