Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([Cl:16])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ncsc2c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
Under a nitrogen atmosphere, benzothiazole-6-carboxylic acid (1.014 g, 5.6 mmol) was dissolved in methylene chloride (25 mL). Five drops of N,N-dimethylforamide was added. Oxalyl chloride (0.5 mL, 5.6 mmol) was slowly added. After 2 hrs, the reaction was heated to 30° C. for 16 hrs. The reaction was concentrated in vacuo to yield benzothiazole-6-carbonyl chloride (1.665 g, quant., light yellow powder)
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:22].O>CN(C)C=O>[CH3:22][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][S:2][CH3:1])[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: C[S-]
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCCCn1c(C)nc2cnc3ccccc3c21
Yield: 95.9 %

Procedure:
Sodium thiomethoxide (2.02 g of 95%, 27.40 mmol) was added in a single portion to a solution of 1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline (5.0 g, 18.26 mmol) in anhydrous N,N-dimethylformamide (91 mL). After 30 minutes the reaction mixture was poured with rapid stirring into water (500 mL). The resulting solution was extracted with chloroform (2×200 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) then with brine (100 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide 5.0 g 2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinoline as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15]C(C)(C)[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O.[ClH:48].[Na+].[Cl-]>O1CCOCC1.O>[ClH:48].[C:1]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]([OH:15])=[C:13]([CH:12]=2)[C:18]([OH:19])=[O:17])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(C)(C)C)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(C)(C)C)cc3)c3ccc(O)c(C(=O)O)c3)cc2)cc1
Temperature: 80 °C
Yield: 64 %

Procedure:
To a solution of 6-((4-tert-butylbenzyl){4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (71 mg, 0.12 mmol) in dioxane (2 ml) was added a solution of LiOH hydrate (25 mg, 0.60 mmol) in water (0.2 mL). The reaction mixture was heated at 80° C. for 3 hrs. Then a solution of HCl in dioxane (1 mL, 4N) and a saturated aqueous solution of NaCl (5 mL) were added and extracted with Et2O (2×10 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure. The residue was dissolved in a solution of HCl in Et2O (1 mL, 1N) and DCM (1 mL). Evaporation of the solvent under reduced pressure gave 57 mg (64%) of the title compound as a beige solid. HPLC, Rt: 5.7 min (purity: 79.0%). 1H NMR (CDCl3) δ: 8.08-6.85 (m, 15H), 4.69 (brs, 4H), 2.61 (t, J=7.7 Hz, 2H), 1.59 (m, 2H), 1.34 (m, 2H), 1.24 (s, 9H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH:26]=[CH:25]3)=[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][N:33](CC4C=CC=CC=4)[CH2:32][CH2:31]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH:26]=[CH:25]3)=[C:17]([NH:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCN(Cc4ccccc4)CC3)c3ncn(C4C=CCC4)c3n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4C=CCC4)c3n2)CC1

Procedure:
Add to a solution of trans-{4-[6-(1-benzyl-piperidin-4-ylamino)-9-cyclopent-2-enyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8c, 1.0 mmol) in 40 mL of methanol, a suspension of Pd black (0.5 wt %) in a small amount of water. Then add a solution of ammonium formate (2.2 mmol) in 10 mL of water, and heat at a gentle reflux overnight. Remove the catalyst by filtration through Celite® and concentrate the filtrate. Dissolve the residue in DCM and extract with water. Remove the white precipitate by filtration through a pad of Celite®, wash the filtrate with brine, dry over sodium sulfate and filter. Concentrate the filtrate and purify the residue on silica gel (50 g) using DCM:methanol (4:1) to give trans-{4-[9-cyclopent-2-enyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9c).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH:11]([N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Na+].Cl[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1>CN(C)C=O>[C:36]1([CH2:35][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:10][CH:11]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[C:12]2=[O:20])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1
Reactant: ClCc1nccc2ccccc12
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nccc2ccccc12
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To a suspension of sodium hydride (0.11 g in a 64% dispersion of mineral oil) in dry N,N-dimethylformamide (20 ml) was added slowly (3RS)-2,3-dihydro-5-phenyl-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.00 g) at ambient temperature, and stirred for 2 hours. To the mixture was added sodium iodide (0.413 g) and followed dropwise a solution of 1-chloromethylisoquinoline (0.695 g) in dry N.N-dimethylformamide (5 ml) at ambient temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was taken up with ethyl acetate. The organic layer was washed with saturated sodium carbonate aqueous solution, and dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. The crude product was purified by column chromatography with chloroform as an eluent to give (3RS)-2,3-dihydro-1-(isoquinolin-1-yl)methyl-5-phenyl-3-phthalimido-1H-1,4-benzodiazepin-2-one (0.54 g) as a colorless form.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][N:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)C(=O)C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][CH2:30]OCC>>[CH2:29]([C:21]1[CH:20]=[C:19]([NH:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH3:30]
Reactant: CC(=O)N(CCc1ccccc1)c1ccnc2ccccc12
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cc(NCCc2ccccc2)c2ccccc2n1
Yield: 36.7 %

Procedure:
To a suspension of 0.59 g of lithium aluminum hydride in 100 mL of dry ether was added, dropwise, a solution of 2.3 g of N-(2-phenylethyl)-N-(4-quinolinyl)acetamide dissolved in 50 mL of dry ether. The mixture was heated to reflux for seven hours. Excess lithium aluminum hydride was then destroyed by adding 100 mL of water to the mixture. The solvent was then removed, and the residue was dissolved in chloroform. After washing with water, the mixture was then dried and concentrated. Using HPLC (silica gel, CH2Cl2 →EtOAc), 0.80 g of the title product was isolated. Yield 36.7%. M.P. oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:39](Cl)(=[O:41])[CH3:40]>>[C:39]([NH:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4])(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using acetyl chloride. The final product was obtained in 38% yield.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].Cl[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[NH4+]>O1CCCC1>[CH3:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:2][CH3:3]
Reactant: CCBr
Reactant: CCCCCCCCCC/C=C\CCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC/C=C\CCCCCCCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 915.2 %

Procedure:
A 1-liter reactor was charged with 5.0 g (0.206 mole) of magnesium and 90 g of tetrahydrofuran, and the reaction was initiated by adding 2 g of ethyl bromide and 46 g (0.2 mole) of 1-chloro-cis-3-tetradecene dropwise thereto under an atmosphere of nitrogen. After completion of the addition, the mixture was stirred for 2 hours under reflux of tetrahydrofuran and the resulting liquid was transferred to a 300-ml dropping funnel. Next, 30 g of tetrahydrofuran, 0.5 g of cuprous bromide and 22 g (0.204 mole) of ethyl bromide were placed in another 1-liter reactor and cooled to 0° C. Then, the above-described Grignard reagent was added dropwise thereto so that the temperature did not exceed 10° C. After completion of the reaction, 100 g of a saturated aqueous ammonium chloride solution was added and the resulting mixture was allowed to separate into two layers. The organic layer was recovered, freed of tetrahydrofuran under reduced pressure, and distilled to obtain 37.7 g of cis-5-hexadecene (purity 96%, yield 81%, b.p. 149°-152° C./3 mmHg). MS(m/e): 56(100%), 224 (M+, 21%).
Reaction SMILES: [C:1]([O:4][C@@:5]1([CH2:39][CH3:40])[C:36]2[CH:35]=[C:34]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:20](S(C)=O)=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:37])[C:9]=2[CH2:8][O:7][C:6]1=[O:38])(=[O:3])[CH3:2].[CH2:41]([NH2:45])[CH2:42][CH2:43][CH3:44]>O1CCOCC1>[C:1]([O:4][C@@:5]1([CH2:39][CH3:40])[C:36]2[CH:35]=[C:34]3[N:11]([CH2:12][C:13]4[C:14]3=[N:15][C:16]3[C:17]5[C:18]=4[N:19]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:20]([NH:45][CH2:41][CH2:42][CH2:43][CH3:44])=[N:21][C:22]=5[CH:23]=[CH:24][CH:25]=3)[C:10](=[O:37])[C:9]=2[CH2:8][O:7][C:6]1=[O:38])(=[O:3])[CH3:2]
Reactant: CCCCN
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cccc3c1c2N(CCC(C)C)C(S(C)=O)=N3
Solvent: C1COCCO1
Product: CCCCNC1=Nc2cccc3nc4c(c(c23)N1CCC(C)C)Cn1c-4cc2c(c1=O)COC(=O)[C@@]2(CC)OC(C)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
To a solution of (9S)-9-acetoxy-9-ethyl-1-(3-methylbutyl)-2-methylsulfinyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (6.4 mg, 0.01 mmol) in 1,4-dioxane (1.0 ml) was added n-butylamine (30 μl, 0.3 mmol). The mixture was stirred at 100° C. for 5 hr, and then stirred at room temperature for 2 days. After concentrated under reduced pressure, the obtaining residue was purified by column chromatography (dichloromethane/acetone=10/1) to give the product (5.4 mg, 83%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:20]([OH:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].C1C(=O)N([Br:30])C(=O)C1>C(O)(=O)C>[Br:30][C:19]1[CH:18]=[C:17]([Cl:22])[C:3]([CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:6]2=[O:16])=[C:2]([Cl:1])[C:20]=1[OH:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C(Cc2c(Cl)ccc(O)c2Cl)CCN1C1CCCCC1
Solvent: CC(=O)O
Product: O=C1C(Cc2c(Cl)cc(Br)c(O)c2Cl)CCN1C1CCCCC1
Yield: 84.9 %

Procedure:
Place 3-(2,6-dichloro-3-hydroxybenzyl)-1-cyclohexylpyrrolidin-2-one (1.116 g, 3.26 mmol) in acetic acid (5 mL). Add NBS (0.609 g, 3.42 mmol) and stir at room temperature for 2 hours. Pour reaction mixture onto water, filter, and dry to give 1.165 g (85%) of the title compound. Mass spectrum (apci) m/z=422.1 (M+H).
Reaction SMILES: ClC1C=CC(S(Cl)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC=CC=1N.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:43]([O-:45])=[O:44].[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>N1C=CC=CC=1>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:26]([N+:43]([O-:45])=[O:44])[CH:27]=1)(=[O:33])=[O:32]
Reactant: C1CNCCN1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: COc1ccccc1N
Solvent: c1ccncc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(N2CCNCC2)c([N+](=O)[O-])c1

Procedure:
The compound was prepared from 4-chloro-3-nitrobenzenesulfonyl chloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2CL2 (2 mL). 4-Chloro-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamide (0.345 g) was reacted with piperazine (0.111 g) to afford N-(2-methoxyphenyl)-4-(piperazinyl)-3-nitrobenzenesulfonamide. This was then treated with Raney-Ni and hydrazine monohydrate. The final product was isolated as its HCl salt. 1H NMR (DMSO-d6) δ 7.18-7.20 (m, 1H), 7.08-7.10 (m, 2H), 6.93-6.96 (m, 1H), 6.91-6.93 (m, 2H); 6.84 (dt, 1H), 3.56 (s, 3H), 3.22-3.27 (m, 4H), 3.00-3.02 (m, 4H); MS (posESI) m/z=362.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[CH2:22][C:23]1[S:24][C:25]([CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1>N1C=CC=CC=1>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:37])[CH2:22][C:23]1[S:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CO[Si](C)(C)C(C)(C)C)s2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CO)s2)cc1OC
Temperature: 0 °C
Yield: 83.3 %

Procedure:
To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]2-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-thienyl]acetate (400 mg, 0.65 mmol) in pyridine (5 mL) was added HF.pyridine (0.88 mL) drop wise. The resultant solution was stirred at room temperature for 3 h. The reaction solution was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the organic phases combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid (270 mg, 84%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])[CH3:5].C1C(=O)N([Br:27])C(=O)C1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[S:9][C:10]=1[CH2:11][Br:27])[CH3:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1nc(-c2ccc(Cl)cc2)sc1C
Product: COC(=O)C(C)c1nc(-c2ccc(Cl)cc2)sc1CBr

Procedure:
A mixture of methyl-2-(5-methyl-2-(4-chlorophenyl)thiazol-4-yl)propionate (Compound No. 178) (0.5 g, 1.7 mmol), NBS (0.33 g 1.87 mmol), benzoyl perodide (cat.), were irradiated (UV) for 2 hours. The reaction mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The residue on trituration with hexane gave the product (0.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)[CH2:7]1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Degas a mixture of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (245 mg, 1 mmol), 2-bromo-5-nitropyridine (168 mg, 0.83 mmol) and cesium carbonate (404 g, 1.24 mmol) in dry toluene (2 mL) by bubbling nitrogen for 15 min. Add tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.016 mmol) and (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (18 mg, 0.024 mmol). Stir the resulting mixture at 90° C. overnight. Chromatograph on silica gel and concentrate to give the title compound (280 mg, 92%).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:13]([CH:15]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[C:16]2=O)=[O:14])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C(Cl)(=O)C([Cl:32])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:13]([C:15]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[C:16]=2[Cl:32])=[O:14])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)C(=O)C(C)(C)C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)=C(Cl)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.25 g (0.65 mmol) of 2-(8-difluoromethylquinolin-5-yl)carbonyl-4,4,6,6-tetramethyl-cyclohexane-1,3,5-trione was dissolved in 15 ml of dichloromethane and 0.25 g (1.95 mmol) of oxalyl chloride and 7 drops of dimethylformamide were added. The mixture was stirred at 25° C. for 17 hours, after which the solvent was removed. This gave 0.2 g of colorless crystals.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][C:18]([CH3:23])([CH3:22])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][C:18]([CH3:23])([CH3:22])[CH2:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOC(C)(C)C3)c2n1
Reaction time: 4 h
Yield: 52.7 %

Procedure:
A solution of N2-butyl-9-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-8-methoxy-9H-purine-2,6-diamine (73 mg) in MeOH (2 mL) was treated with 4N HCl in 1,4-dioxane (1 mL) and was stirred for 4 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried. The solid was re-precipitated from ether/light petrol to give the title compound (37 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Temperature: 120 °C
Yield: 89.6 %

Procedure:
A mixture of [4-(methylthio)phenyl]boronic acid (66 mg, 0.39 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 140 mg, 0.39 mmol), PdCl2(PPh3)2 (50 mg), 2M Na2CO3 (1 mL) and DME (2 mL) was stirred and heated in a microwave at 120° C. for 10 min, cooled to ambient temperature, and the organics were separated. The aqueous phase was washed with EtOAc. The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexanes to give 140 mg (90%) of 1-methylethyl 4-[({6-[4-(methylthio)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.8 Hz), 7.84 (d, 2H, J=8.5 Hz), 7.60 (d, 1H, J=8.8 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.22 (bs, 1H), 4.90 (septet, 1H, J=6.3 Hz), 4.20 (bs, 2H), 3.87 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.50 (s, 3H), 2.04-1.94 (m, 1H), 1.90-1.75 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 401 (M+H).