Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:21]1[CH:22]=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:21]1[CH:22]([OH:23])[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: COCOCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCOCc1ccc(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
1.6M n-Butyl lithium-hexane solution (104 ml, 167 mmol) was added dropwise to a solution of 1-bromo-4-(methoxymethoxymethyl)benzene (38.6 g, 167 mmol) in tetrahydrofuran (350 ml) at -78° C. in a nitrogen stream over 30 minutes. This reaction solution was stirred at -78° C. for 30 minutes and then a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (27.5 g, 83.5 mmol) in tetrahydrofuran (300 ml) was added dropwise thereto over 1 hour. This reaction solution was stirred at -70° C. for 2 hours and then warmed and saturated aqueous ammonium chloride was added thereto at -20° C. To the reaction mixture, a liquid mixture of ethyl acetate with water was added. The organic layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-[α-hydroxy-4-(methoxymethoxymethyl)benzyl]pyrrolidine (24.1 g, yield: 59.8%) as a colorless oily substance.
Reaction SMILES: C(N(CC)CC)C.N1C(=O)CC[C@H]1C(O)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.O>CS(C)=O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1
Reactant: COc1ccc2ncnc(OCC3CCC(O)CC3)c2c1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2ncnc(OCC3CCC(=O)CC3)c2c1
Reaction time: 0.25 h

Procedure:
Triethylamine (10 ml, 71 mmol) and then, in portions, Pyr.SO3 (5.8 g, 36 mmol), were added at 0° C. to a solution of 4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexanol (2.88 g, 10 mmol) in DMSO (30 ml). The reaction mixture was stirred at that temperature for 15 minutes and then allowed to come to room temperature. After 2 hours, water (300 ml) was added. The aqueous phase was extracted with ether (3×150 ml). The combined organic phases were washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel (EtOAc/hex 1/2).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O-:11].[K+].[C:13](=O)([O-:15])[O-:14].[K+].[K+].[CH:19]([O-:21])=[O:20].[K+]>>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:13]([OH:15])=[O:14])[CH:6]=2)[CH:1]=1.[CH:7]1[CH:6]=[C:5]2[C:10]([CH:1]=[C:2]([OH:11])[C:3]([C:19]([OH:21])=[O:20])=[CH:4]2)=[CH:9][CH:8]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Reactant: O=C[O-]
Agent: [K+]
Product: O=C(O)c1cc2ccccc2cc1O
Product: O=C(O)c1ccc2cc(O)ccc2c1
Reaction time: 5 h
Yield: 5.7 %

Procedure:
The procedure is according to the procedure described in the above examples under a carbon monoxide pressure of 100 bar and at a temperature of 320° C. over a period of about 5 hours, using 10 parts of potassium β-naphtholate, 7.6 parts of potassium carbonate and 75 parts of potassium formate. After working up the reaction mixture, 2-hydroxy-naphthalene-6-carboxylic acid is obtained in a yield of 37.5% of theory, in addition to 5.7% of 2-naphthol-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[OH:16][S:17](O)(=[O:19])=[O:18]>O>[OH:1][C:2]1[C:3]([S:17]([OH:19])(=[O:18])=[O:16])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:7][CH:6]=2
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(S(=O)(=O)O)c(O)cc2c1
Temperature: 115 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
7-Hydroxynaphthalene-2-sulfonic acid (250 g, 1.16 mol) was added in portions to a mixture of concentrated H2SO4 (950 g) and water (50 g). The mixture was stirred at 110-120° C. for 3 hours, cooled to room temperature, added to a mixture of ice and water (5000 ml) and the product precipitated by the addition of sodium chloride. The slurry was warmed to 90° C. to dissolve the product, stirred for 1 hour at this temperature and then allowed to cool. The product was filtered off and the damp product dissolved in water (3000 ml) at pH 10 by the addition of concentrated sodium hydroxide solution. The solution was then filtered to remove a small amount of insoluble material. The pH of the filtrate was lowered to 7 with concentrated HCl and the product precipitated by the addition sodium chloride. The product was filtered off and dried in a vacuum oven to give 117 g of a cream coloured solid (68% yield).
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[Br:11][CH2:12][CH2:13][CH2:14]Br>C(#N)C>[Br-:11].[Br:11][CH2:12][CH2:13][CH2:14][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: CNCCC[N+](C)(C)C
Reactant: BrCCCBr
Agent: [Br-]
Solvent: CC#N
Product: CN(CCCBr)CCC[N+](C)(C)C

Procedure:
To a stirred solution of 3.02 g. (14.3 mmoles) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.88 g. (14.3 mmoles) of 1,3-dibromopropane and the mixture is stirred at room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give the product.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:43]([OH:45])=[O:44])[CH2:41][OH:42]>C(N(CC)CC)C.C1COCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:43]([OH:45])=[O:44])[CH2:41][OH:42])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: N[C@@H](CO)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Yield: 81.5 %

Procedure:
The suspension of mixed anhydride is prepared by using 3.55 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 1.0 g of N-methylmorpholine, 1.4 g of isobutyl chlorocarbonate and 60 ml of THF in the same manner as Example 1. To the suspension 20 ml of the aqueous solution of 2.1 g of L-serine and 2.0 g of triethylamine is added. The mixture is stirred under ice-cooling for 30 minutes and at room temperature for an additional 1 hour. After removing THF in vacuo, it is acidified with N--HCl, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is crystallized from benzene to give 3.6 g (82%) of the titled compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)=[O:2].[OH-].[Na+].C1(C)C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:24][S:23][C:20]1[N:21]=[CH:22][C:11]2[C:10](=[O:25])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[O:2][CH:39]=[N:38][CH:37]=4)[CH:4]=3)[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]=2[N:19]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C=O)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3cnco3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
(S)-5-(3-Formylphenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (380 mg, 1.07 mmol) obtained in Step 2 was dissolved in methanol (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding sodium hydroxide (120 mg, 2.14 mmol) and p-toluenesulfonylmethylisocyanide (230 mg, 1.18 mmol). After diluting the mixture with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(1,3-oxazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (300 mg, 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[C:29]2[CH:37]([F:39])[F:38])[N:17]=1.CCN(CC)CC>C1COCC1.O>[F:39][CH:37]([F:38])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])(=[O:6])=[O:7])[CH2:9][CH2:10]3)[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1
Reactant: CN(C)CCS(=O)(=O)N1CCNCC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
A mixture of the above amine (1.35 g, 6 mmol) and 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (International Publ. No. WO 2002/088112, the disclosure of which is incorporated herein by reference in its entirety) (1.83 g, 5 mmol) and Et3N (1.4 mL, 10 mmol) in 50 mL THF was stirred at room temperature for 5 hrs and then diluted with water. The white solid was collected and dried. Chromatography on alumina, eluting with CH2Cl2 gave 1.42 g (43% yield) of N-[2-({4-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)ethyl]-N,N-dimethylamine: 1H NMR (CDCl3) δ 7.86 (br dd, J=7.1, 1.2 Hz, 1H), 7.89 (br dd, J=6.8, 1.2 Hz, 1H), 7.53 (t, JHF=53.5 Hz, 1H), 7.46-7.38 (m, 2H), 4.00 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.40 (m, 4H), 3.21 (dd, J=8.1, 6.4 Hz, 2H), 2.78 (dd, J=8.1, 6.4 Hz, 2H), 2.27 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.CN.[CH:22]([N:25](CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Agent: CN
Agent: Cl
Solvent: CO
Product: CNc1nc(Cl)nc2c1COCC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation I) (194 mg, 0.690 mmol) in MeOH (6901 μL) was added methanamine hydrochloride (69.9 mg, 1.035 mmol) and N,N-Diisopropylethylamine (301 μL, 1.725 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 2-chloro-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (126 mg, 0.457 mmol, 66.2% yield). LC-MS (M+H)+=276.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.28 (2 H, t, J=7.32 Hz), 7.20-7.25 (1 H, m), 7.14-7.20 (2 H, m), 4.47-4.62 (2 H, m), 4.47 (1 H, s), 4.00-4.11 (2 H, m), 3.95 (1 H, d, J=3.36 Hz), 3.08 (3 H, d, J=4.88 Hz).
Reaction SMILES: N[C@H](CCC1C=CC=CC=1)CO.[C:13]([O:17][C:18](=[O:44])[N:19]([CH2:31][CH2:32][C:33](=[O:43])[NH:34]OCC1C=CC=CC=1)[C@H:20]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21]O)([CH3:16])([CH3:15])[CH3:14].C(OC(N1CCC(=O)N(OCC2C=CC=CC=2)C[C@H]1CCC1C=CC=CC=1)=O)(C)(C)C>>[C:13]([O:17][C:18]([N:19]1[CH2:31][CH2:32][C:33](=[O:43])[NH:34][CH2:21][C@H:20]1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:44])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NOCc1ccccc1)[C@@H](CO)CCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(=O)N(OCc2ccccc2)C[C@H]1CCc1ccccc1
Agent: N[C@@H](CO)CCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=O)NC[C@H]1CCc1ccccc1

Procedure:
The title compound, m/e=444.3, was produced in analogy with intermediate 16, steps A to D. Thus, (R)-2-amino-4-phenylbutan-1-ol was elaborated to (2-benzyloxycarbamoyl-ethyl)-((R)-2-hydroxy-1-phenethyl-ethyl)-carbamic acid tert-butyl ester in step A, then cyclized in step B, leading to (R)-4-benzyloxy-5-oxo-2-phenethyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester. Hydrogenation in step C gave (R)-5-oxo-2-phenethyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester, which was alkylated with 1-(3-chloropropyl)piperidine in step D.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][S:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2CC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of step f) (10 mg, 0.039 mmol) dissolved in a 50:50 mixture of chloroform/acetic acid (1 ml) was treated with N-bromosuccinimide (7 mg, 0.041 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was poured into water (5 ml) and extracted with CHCl3 (3×5 ml). The combined organic phases were washed with 10% KOH solution (5 ml), brine (5 ml), dried (MgSO4), and concentrated to give the crude product as an oil. Purification by HPLC gave the subtitle compound as an oil. MS: ESI (positive): 332, 334 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[CH:11]=1)(=[O:9])=[O:8].Br[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=1[O:48][CH:49]([F:51])[F:50].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)(C)(C)C.O1CCOCC1>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=2[O:2][CH3:1])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:9])=[O:8])=[CH:11]3)=[C:42]([O:48][CH:49]([F:50])[F:51])[CH:43]=1
Reactant: FC(F)Oc1cc(Cl)ccc1Br
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC(F)F)cccc3c2)c(OC)c1
Temperature: 100 °C

Procedure:
A microwave vial was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate E) (130 mg, 0.229 mmol), 1-bromo-4-chloro-2-(difluoromethoxy)benzene (Intermediate J) (118 mg, 0.458 mmol) and Pd(dppf)Cl2DCM (37.4 mg, 0.046 mmol). Dioxane (1145 μl) and t-butanol (1145 μl) were added to the reaction vial followed by sodium carbonate in water (362 μl, 0.687 mmol, 1.9 M). The vial was purged with nitrogen and sealed. The mixture was stirred and sonicated for 5 min. The resulting light red mixture was then heated in a microwave at 100° C. for 30 min LC/MS indicated complete conversion of boronic ester to the desired product. The reaction was cooled to rt and filtered through a fritted funnel with an aid of DCM (15 mL). The filtrate was acidified with 2N aqueous HCl to a pH of about 1. After stirring for 5 min at room temperature, the product was extracted with DCM (2×20 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated to afford a dark oil. MS (ESI): 639.8 [M+Na]+
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)=[O:26])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCCCSc1cccc2nccn12
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCS(=O)c1cccc2nccn12
Yield: 17.9 %

Procedure:
To a solution of 5-[3-(acetyloxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 3.99 mmoles) in chloroform (25 ml) was added m-chloroperbenzoic acid (1.47 g, 5.96 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 1.5 hours. The reaction mixture was washed in turn with an aqueous 20% sodium bisulfite solution and an aqueous saturated sodium bicarbonate solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent:hexane/acetone (1:1)] to obtain 0.19 g of 5-[3-(acetyloxy)propylsulfinyl]imidazo[1,2-a]pyridine (Compound 177) (34.6%, yellow oily product) and 0.19 g of 5-(acetyloxy)propylsulfonyl]imidazo[1,2-a]pyridine (Compound 178) (16.5%, yellow oily product).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27][C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]1(CO)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:27][CH2:25][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: OCC1CCCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCCCC4)c(Cl)c3)c2cc1OC
Yield: 75.9 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclohexylmethanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (54 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[OH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(O)(=O)C.[Na]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([OH:25])[CH2:27]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OC1CCCNC1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NCCCN1CCCC(O)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (0.13 g, 0.32 mmol) and 3-hydroxy-piperidine (89.0 mg, 0.38 mmol) in tetrahydrofuran (3.0 mL) under nitrogen, was added acetic acid (0.2 mL). The resulting mixture was stirred at ambient temperature for 30 minutes. Then sodium triacetoxyboronhydride was added and the reaction mixture was stirred at ambient temperature for additional 4 hours. After this time, the reaction mixture was diluted with water and extracted with ethylacetate. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 90:10 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (14.0 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.83 (1H, m), 8.41 (1H, s), 4.58 (1H, m), 3.19 (2H, m), 2.80 (1H, m), 2.61 (1H, m), 2.27 (2H, m), 1.76 (2H, m), 1.61 (3H, m), 1.38 (1H, m), 1.23 (1H, m), 1.06 (1H, m). MS m/z: 491.11, 493.13 [M+H]+.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 105.3 %

Procedure:
As described in Example 3, 8.92 g of methyl bromo{p-[(p-chlorophenoxy)methoxy]phenyl}acetate, 3,45 g of p-tert.-butylphenol and 9.17 g of 60% sodium hydride-oil dispersion are reacted in 75 ml of tetrahydrofuran containing 1 ml of hexamethylphosphoramide and worked-up to give 11 g of product as an oil. Chromatography over silica gel with dichloromethane as eluent gives 7.1 g of gum which is crystallized from methanol to give 4.9 g of white crystals. Recrystallization gives white crystals, mp 64°-65° C.