Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].CCOCC>O1CCOCC1.O.Cl.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]3)[CH:36]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Reactant: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccccc2-c2ccnc(N3CCNCC3)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 46.9 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (51.1 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (3 ml) and 1N HCl (1 mL). The mixture was then filtered to remove residual salts and purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)). The title compound, N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({2-[2-(1 -piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (52 mg. 0.083 mmol, 47.0% yield), was obtained as a white solid (tfa salt) after trituration with ether. 1H NMR (400 MHz, DMSO-d6) d ppm 15.83 (s, 1 H), 13.02 (br. s., 1H), 10.07 (t, J=5.43 Hz, 1H), 8.79 (br. s., 2H), 8.19 (d, J=5.05 Hz, 1H), 7.39 (dd, J=5.68, 3.41 Hz, 2H), 7.24-7.31 (m, 1H), 7.21 (dd, J=5.43, 3.66 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J=5.05 Hz, 1H), 5.30 (s, 2H), 4.08 (d, J=5.56 Hz, 2H), 3.69-3.85 (m, 4H), 3.20 (br. s., 4H), 3.12 (m, 1H), 1.12 (d, J=6.82 Hz, 6H). MS (ES+) m/e 507 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[H][H]>[Pd].C(O)C.C(#N)C.O>[N:3]1[CH:2]=[CH:7][C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccncc1
Reaction time: 16 h

Procedure:
A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (165 mg, 0.363 mmol) and 10% palladium on carbon (77 mg) in ethanol (10 mL) was placed under 1 atmosphere of hydrogen (balloon). After 16 hours, diatamacous earth (300 mg) was added and the mixture and the solution was filtered through diatamacous earth and concentrated to afford an oil. The crude material was dissolved in a 4:1 mixture of acetonitrile in water and purified by reversed-phase HPLC. The desired fractions from the column were concentrated to remove the acetonitrile, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:21]#[N:22].Cl.N1C=CC=CC=1.[OH-].[NH4+]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:21]#[N:22]
Reactant: COc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3ccc(O)cc3cc2c1Nc1ccc(Cl)cc1Cl
Temperature: 215 °C
Reaction time: 0.83 h

Procedure:
A reaction mixture of 566.5 mg (1.44 mmol) of 4-(2,4-dichloroanilino)-7-methoxybenzo[g]quinoline-3-carbonitrile and 10 g of pyridine hydrochloride is stirred at 215° C. for 50 min under nitrogen. After cooling, the mixture is neutralized with 40 mL of a 3% ammonium hydroxide solution and stirred for 0.5 hour. The separated solid is filtered off and washed with water and ether. After drying in vacuo, this yields 527.9 mg (96.5%) of 4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile as a salmon color solid, mp>300° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].CC[O:11][C:12]([CH3:14])=[O:13]>C(OC(=O)C)(=O)C>[C:12]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:14]
Reactant: Cc1cccc[n+]1[O-]
Reactant: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccccn1

Procedure:
A solution of the 2-methylpyridine N-oxide (1.0 mmol) in acetic anhydride (5 mL) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSO4), evaporation and purification by preparative TLC or flash chromatography afforded the 2-(acetoxymethyl) pyridine.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](OCC)(=[O:9])/[CH:6]=[CH:7]/[CH3:8]>CO>[CH3:8][CH:7]1[NH:4][CH2:1][CH2:2][NH:3][C:5](=[O:9])[CH2:6]1
Reactant: NCCN
Reactant: C/C=C/C(=O)OCC
Solvent: CO
Product: CC1CC(=O)NCCN1

Procedure:
Ethane-1,2-diamine (1.35 g, 22.44 mmol) and (E)-ethyl but-2-enoate (2.56 g, 22.44 mmol) in MeOH (22 mL) was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and crude product purified by chromatography on silica gel with a gradient of DCM to DCM:2M NH3/MeOH (4:1, v/v) as eluent. This afforded a mixture of desired product and uncyclised material. The mixture was diluted with MeOH (4 mL) and heated in the microwave at 150° C. for 10 min followed by 160° C. for 10 min. Sodium bicarbonate (100 mg) was added and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was filtered, solvent evaporated under reduced pressure and crude product purified by chromatography on silica gel with a gradient of DCM to DCM:2M NH3/MeOH (4:1, v/v) as eluent to afford 7-methyl-1,4-diazepan-5-one (310 mg, 2.42 mmol, 11%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([OH:16])=[CH:7][C:8]([CH:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:24].[N:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:24].[CH3:23][C:2]1([CH3:1])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([O:16][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:7][C:8]([CH:10]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CC1CC1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(CC1CC1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-cyclopropyl-2-propyl)-10-[4-(piperidino)-butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-cyclopropyl-2-propyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl-carbodiimide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Br[C:20]1C=C(C=CC=1)C(OCC)=O.CC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:20])[CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(-c2ccc(C)cc2)c1
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-c2cccc(C)c2)c1

Procedure:
3′-Methyl-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-methyl-biphenyl-3-carboxylic acid ethyl ester. Ethyl 3-bromobenzoate (3.83 g, 16.72 mmol, 1 eq.) and 3-methylbenzeneboronic acid (2.5 g, 18.39 mmol, 1.1 eq.) in THF were treated with aqueous sodium carbonate (2M solution, 18.4 mL, 36.78 mmol, 2.2 eq.), palladium(II) acetate (0.37 g, 1.67 mmol, 10 mol %), triphenylphosphine (1.93 g, 7.35 mmol, 4.4×Pd), and copper(I) iodide (0.1 g, catalyst). When complete, the reaction was worked up as described leaving a brown oil.
Reaction SMILES: COC(=O)[C:4]([C:11]#[N:12])=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.Cl>[OH-].[Na+]>[NH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]1=[CH:4][C:11]#[N:12]
Reactant: COC(=O)C(C#N)=C1CCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC=C1CCCCN1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A suspension of cyano-2-piperidinylidene-ethanoic acid methyl ester (1.4 g, 7.76 mmol) in 25 mL 1M NaOH was heated at 100° C. for 30 mins. The reaction mixture was cooled to 0° C. and acidifed to pH 5-6 by adding conc. HCl, then extracted with 3×50 mL acetate. The organic phases were combined, dried, and concentrated. The crude product was purified on flash column to afford 2-piperidinylidene-ethanenitrile (590 mg, 62%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17]Cl)[CH3:15])[CH2:3]1.O.C(=O)([O-])[O-].[K+].[K+].[N-:26]=[N+:27]=[N-:28].[Na+]>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][N:26]=[N+:27]=[N-:28])[CH3:15])[CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
4.5 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chlo roethyl)-N-methylamine were added to a mixture of 40 ml water and 20 ml tetrahydrofuran. 2 g of potassium carbonate and 1 g of sodium azide were added to the mixture. The reaction solution was then stirred at room temperature for 8 hours. The reaction solution was worked up by concentrating to about 30 ml and extracting the aqueous phase with ethyl acetate. After concentration of the ethyl acetate extract, 4.5 g of crude N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-ylo xy)ethyl]-N-(2-azidoethyl)-N-methylamine were obtained, which was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl.CO>ClCCCl>[C:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:23][CH:22]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of the product of Example 9 (4.0 g, 8.0 mmol) stirring in 1,2-dichloroethane (50 mL) at 0° C. was added boron trichloride (10 mL, 117.0 mmol). The resulting dark purple solution was stirred at room temperature overnight in a sealed tube then cooled to 0° C. Methanol (50 mL) was carefully added dropwise over a 30 minute period (caution: gas evolution). The resulting solution was concentrated and dissolved in ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated. The resulting brown foam was purified by flash chromatography (silica gel, methanol/chloroform gradient) to give 2.7 g (63%) of desired product as a white foam: 1H-NMR (300 MHz, DMSO) δ9.72 (br s, 1H), 7.62-7.80 (m, 2H), 7.22-7.50 (m, 6H), 7.10-7.22 (m, 2H), 7.00 (m, 1H), 6.80-6.90 (m, 2H), 6.78 (m, 1H), 4.23 (s, 2H), 3.85-4.10 (m, 2H), 2.50-2.75 (m, 2H), 2.25-2.50 (m, 4H), 1.25-1.56 (m, 6H); Anal. Calc'd. for: C, 82.35; H, 7.14; N, 3.20. Found: C, 82.17; H, 7.11; N, 3.35; MS (FD) m/e 437 (M+); IR (KBr) 2935.07, 2855.01, 1621.38, 1597.26 cm-1.
Reaction SMILES: IC1C2N=C(SC)N=C(NC3C=CC(OC4C=CC=CC=4)=CC=3)C=2C(=O)NC=1.C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].CS[C:46]1[N:47]=[C:48]([NH:63][C:64]2[CH:69]=[CH:68][C:67]([O:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:66][CH:65]=2)[C:49]2[C:55](=[O:56])[NH:54][CH:53]=[C:52]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:50]=2[N:51]=1.[OH:77][CH:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1>O1CCOCC1>[OH:77][CH:78]1[CH2:83][CH2:82][N:81]([C:46]2[N:47]=[C:48]([NH:63][C:64]3[CH:65]=[CH:66][C:67]([O:70][C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)=[CH:68][CH:69]=3)[C:49]3[C:55](=[O:56])[NH:54][CH:53]=[C:52]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:50]=3[N:51]=2)[CH2:80][CH2:79]1
Reactant: CSc1nc(Nc2ccc(Oc3ccccc3)cc2)c2c(=O)[nH]cc(-c3ccccc3)c2n1
Reactant: OC1CCNCC1
Agent: CSc1nc(Nc2ccc(Oc3ccccc3)cc2)c2c(=O)[nH]cc(I)c2n1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2ccccc2)c2nc(N3CCC(O)CC3)nc(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 80 °C

Procedure:
A 20 mL reaction vessel was charged with 2-(methylthio)-4-(4-phenoxyphenyl amino)pyrido[4,3-d]pyrimidin-5(6H)-one (221a, 182 mg, 0.48 mmol) and N-iodosuccinmide (158 mg, 0.70 mmol) in 8 mL dry DMF. The reaction mixture was stirred at 60° C. for 2 hours. The solvent was removed under reduced pressure yielding the pale brown solid (221b) after being recrystallized from acetonitrile (210 mg, 87%). A 20 mL reaction vessel was charged with 8-iodo-2-(methylthio)-4-(4-phenoxyphenylamino)pyrido[4,3-d]pyrimidin-5(6H)-one (221b, 52 mg, 0.10 mmol), benzenboronic acid (18 mg, 0.15 mmol), tetrakis(triphenyphosphine)palladium (0) (6 mg, 0.005 mmol), and 2.0 M aq. sodium carbonate solution in 6 ml dioxane. The mixture was purged with nitrogen for 30 min. Then the reaction mixture was heated at 80° C. for 3 h. The solvent was removed under reduced pressure yielding the brown residue. The residue was purified by silica gel chromatography using a gradient of 0-5% MeOH in dichloromethane yielding 221c. Then 221 was prepared as described in Example 1g starting from 2-(methylthio)-4-(4-phenoxyphenylamino)-8-phenylpyrido[4,3-d]pyrimidin-5(6H)-one, and 4-hydroxypiperidine to give title compound. MS m/z: 506 (M+H)+.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])[CH2:4][CH2:3]1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19].O.O.O.C([O-])(=O)C.[Na+].O>CO>[ClH:1].[ClH:1].[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:18][CH2:19][N:2]1[CH2:3][CH2:4][CH:5]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])[CH2:6][CH2:7]1
Reactant: O=C1c2ccccc2CC1C1CCNCC1
Reactant: C=Cc1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2CC1C1CCN(CCc2ccccn2)CC1

Procedure:
A mixture of 0.251 g (0.001 mol) of 2-(4-piperidyl)-1-indanone hydrochloride, 0.21 g (0.002 mol) of 2-vinylpyridine, 0.272 g (0.002 mol) sodium acetate trihydrate, 2 mL of water, and 2 mL of methanol was stirred and refluxed for 20 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and dried over magnesium sulfate. The product was isolated in pure form by chromatography on silica gel using 5% methanol in chloroform. A hydrochloride salt was prepared and was recrystallized from ethanol to give 2-[1-(2-pyridylethyl)-4-piperidyl]-1-indanone dihydrochloride, mp 195°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2nc(COc3ccccc3)c(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CCc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2ccccc2)cc1C
Temperature: 25 °C
Yield: 34.5 %

Procedure:
3-(4-Mercapto-2-methyl-phenyl)-propionic acid-methyl ester (126 mg, 0.600 mmol) is dissolved into anhydrous acetonitrile (ACN) (2 mL). Cesium carbonate (326 mg, 1.00 mmol) is added to the reaction, followed by the addition of 5-Chloromethyl-4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole (200 mg, 0.5211 mmol). The reaction is allowed to stir under nitrogen at room temperature and monitored by TLC and HPLC. Upon complete consumption of the chloride, the reaction is diluted with diethyl ether and quenched with 0.1N NaOH. The two phases are separated, then the organic layer washed with water and brine. The organic phase is dried over anhydrous sodium sulfate and concentrated under vacuum. The residue is further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes (1:9) gradients on silica gel chromatography to yield 3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionic acid methyl ester (100 mg, 0.1796 mmol) or 30%.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH:13]([F:15])[F:14])[CH:5]=1)[CH:2]=C.N1C=CC=CC=1.[O:22]=[O+][O-]>C(Cl)Cl.CO>[F:14][CH:13]([F:15])[O:12][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[O:22])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C=CCc1ccc(C#N)c(OC(F)F)c1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: N#Cc1ccc(CC=O)cc1OC(F)F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4-allyl-2-(difluoromethoxy)benzonitrile (600 mg, 2.9 mmol) in 1:1 CH2Cl2/MeOH (15 mL) containing pyridine (0.5 mL, 6 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl, aqueous NaHCO3, dried and concentrated to give crude 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[I-].[CH3:12][CH2:13][CH3:14].O>CN(C=O)C>[CH3:12][CH:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH3:14]
Reactant: CCC
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OC(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
5-Hydroxy-2-methylpyridine (11.0 g, 100 mmol) was dissolved in N,N′-dimethylformamide (100 mL). The resultant mixture was added with sodium hydride (7.2 g, 150 mmol) and 1-methylethane iodide (12 mL, 121 mmol) under ice-cold conditions, and stirred at room temperature overnight. Subsequently, 1-methylethane iodide (4 mL) was added and the resultant mixture was stirred at 60° C. for 4 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was washed with brine, dried using sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine (12.7 g, yield 84%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccccc3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.5 g, 2.436 mmol) and 2-fluoro-nitro-benzene (0.257 ml, 2.436 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (0.67 g, 4.87 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[N:15]1([C:21]([S:23][CH3:24])=[S:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:18]2[CH2:19][CH2:20][N:15]([C:21]([S:23][CH3:24])=[S:22])[CH2:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
In a nitrogen atmosphere, 2.00 g (14.5 mmol.) of 4-methoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. Under chilling with ice, to thesolution was dropwise added a solution of 1.05 ml (14.5 mmol.) of thionyl chloride in 2 ml of dichloromethane. The mixture was then stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was mixed with 2.90 g (14.5 mmol., purity 88.1%) of methyl 1-piperazinecarbodithioate, 1.54 g (14.5 mmol.) of anhydrous sodiumcarbonate and 25 ml of ethanol. The mixtrue was refluxed under heating for 14.5 hours. The solvent was distilled off under reduced pressure. The residue was mixed with 10 ml of dichloromethane and 10 ml of water. The mixture was allowed to give separated layers, and filtered to remove insolubles. The organic solvent portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Theresidue was purified over a silica gel column to give 1.46 g of methyl 4-(4-methoxybenzyl)-1-piperazinecarbodithioate as a pale yellow oil, yield33.9%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].O[C@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C@@H:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](O)c3ccccc3)CC2)c1
Product: CC(=O)c1ccccc1O[C@H](CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure B and Scheme B1 using 1-(2-hydroxyphenyl)ethanone and N-(3-{1-[(2R)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 485.2 (M+H)+.