Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([Cl:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([Cl:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F)c1[nH]cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (94 mg, 0.161 mmol) in DCM (6 ml) was added TFA (3.0 ml) and the reaction mixture was stirred at rt for 1 hour. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (45 mg, 0.099 mmol, 62% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.70 (s, 1H), 7.25-7.39 (m, 2H), 6.76 (s, 1H), 6.56 (s, 1H), 6.53 (s, 1H), 4.63 (s, 2H), 1.67-2.00 (m, 1H), 0.96 (dd, 2H), 0.63 (dd, 2H). LC-MS (ES+) m/z 454.02, [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:13].[CH:15](O)([OH:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC.C(OCC)C>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:5]3([O:17][CH2:15][CH2:16][O:13]3)[CH2:6][CH2:7][S:8][C:9]2=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(O)O
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: COC(OC)OC
Solvent: O
Product: Cc1cc(Br)c(C)c2c1SCCC21OCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
58.4 g (0.22 mol) of 6-bromo-5,8-dimethyl-4-thiochromanone were dissolved in 380 ml of trimethyl orthoformate, admixed with 555 g (8.9 mol) of ethanediol and 0.2 g of p-toluenesulfonic acid monohydrate and stirred at 80° C. overnight. The mixture was subsequently allowed to cool, diluted with 500 ml of diethyl ether and washed with a 1:1 mixture of 1 M aqueous sodium hydroxide solution and sat. NaCl solution (2×500 ml) and subsequently with sat. NaCl solution (300 ml). The organic phase was dried over MgSO4 and concentrated using a rotary evaporator. The residue was taken up in 50 ml of heptaneldiethyl ether (9:1) and stored in a cold place. The crystals which had precipitated overnight were filtered off with suction, washed with cold heptane and dried.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][C@@H:10]2[O:9][C@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:23]2[O:24][C:25](=[O:27])[CH3:26])=[CH:31][CH:30]=1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Yield: 100.5 %

Procedure:
To a solution of galactose pentaacetate (3.30 g, 8.50 mmol) and 4-hydroxy-thiophenol (1.40 g, 11.1 mmol) in 50 mL of methylene chloride at -78° C. is added boron trifluoride diethyl ether complex (2.10 mL, 17.1 mmol ). The solution is allowed to warm slowly to 0° C. and then stirred for an additional hour at 0° C. The mixture is poured into saturated aqueous NaHCO3 (200 mL) and extracted with CH2Cl2 (2×150 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (50% EtOAc/hexane) to give 3.90 g (99%) of 1-deoxy-1-(4-hydroxyphenylthio)-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 78 as a white solid: Rf 0.3 (50% EtOAc/hexane); 1H NMR (CDCl3, 300 MHz) δ 7.42 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 5.78 (br s, 1H), 5.39 (d, J=2.56 Hz, 1H, H-4), 5.15 (t, J=9.9 Hz, 1H, H-2), 5.00 (dd, J=3.3, 9.9 Hz, 1H, H-3), 4.56 (d, J=9.9 Hz, 1H, H-1), 4.19 (dd, J=6.6, 11.0 Hz, 1H), 4.09 (dd, J=6.6, 11.0 Hz, 1H), 3.89 (t, J=6.6 Hz, 1H, H-5), 2.12 (s, 3H, OAc), 2.09 (s, 3H, OAc), 2.05 (s, 3H, OAc), 1.97 (s, 3H, OAc).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[NH3:36].CO>>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:21][CH2:22][CH2:23]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Solvent: CO
Product: Nc1nccc(-c2sc(C3CCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.20 g, 0.36 mmol) and 7N ammonia in MeOH (10 ml, 70 mmol) the title compound was obtained (0.030 g, 0.056 mmol, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.64 (dd, J=14.3, 2.0 Hz, 1H), 7.55-7.38 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.18 (t, J=9.1 Hz, 2H), 6.72 (br, 2H), 5.61 (d, J=5.1 Hz, 1H), 3.83 (quin, J=8.4 Hz, 1H), 3.45-3.19 (m, 1H), 2.38 (q, J=8.5 Hz, 1H), 2.24 (quin, J=9.1 Hz, 1H), 2.10-1.92 (m, 1H), 1.86 (q, J=9.4 Hz, 1H), 1.06 (t, J=7.0 Hz, 1H). MS (ESI): 534 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:36][NH:37][S:38](Cl)(=[O:40])=[O:39].[OH-].[Na+].[Cl-].[NH4+]>ClCCl.O1CCOCC1>[CH3:36][NH:37][S:38](=[O:40])(=[O:39])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2c(F)cc(F)cc2F)c2cc[nH]c2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)Nc1ccc(Oc2c(F)cc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.6 %

Procedure:
To a mixture of Example 94b (76.3 mg, 0.198 mmol) and triethylamine (60.1 mg, 0.594 mmol) in dichloromethane (4 mL) was added dropwise methylsulfamoyl chloride (103 mg, 0.792 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with dioxane (5 mL) and 1M aqueous sodium hydroxide (3 mL, 0.2 mmol) and heated at 70° C. for 1 hour. The reaction mixture cooled to ambient temperate and then neutralized with saturated aqueous ammonium chloride (50 mL) and the aqueous extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to provide the title compound (11 mg, 11% yield). 1H NMR (300 MHz, DMSO-d6) ppm 12.04 (bs, 1H), 9.58 (s, 1H), 7.43-7.32 (m, 6H), 7.32-7.16 (m, 1H), 7.10 (dd, J=8.8, 2.7 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.23 (t, J=2.3 Hz, 1H), 3.57 (bs, 3H), 2.35 (d, J=4.9 Hz, 3H). MS (ESI+) m/z 479.1 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[CH:23](O)([CH3:25])[CH3:24].O>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)O
Reactant: O=C(O)c1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
CDI (2.34 g, 14.48 mmol) was added to a solution of salicylic acid (2.00 g, 14.48 mmol) in DMF (40 mL). The reaction mixture was stirred at 50° C. for 4 h and isopropyl alcohol (2.80 mL, 36.20 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×40 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.395 g of isopropyl 2-hydroxybenzoate (colourless oil, yield: 54%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](N)[N:3]=1>N1C=CC=CC=1>[N:3]1[C:4]2[C:5](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:6]=[CH:7][CH:2]=1.[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Nc1cccc(N)n1
Solvent: c1ccncc1
Product: c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 2 was redissolved in five milliliters of anhydrous pyridine, To this was added 74 millgrams of 2,6-diaminopyridine and the mixture was stirred at amient temperature for 18 hours. The reaction mixture was then stirred at 100° C. for two hours and allowd to cool to room temperature. The solvent was removed in a rotary evaporator and the produce was washed with methanol. 420 milligrams of the copolymer was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:18])[NH:14][CH2:15]OC)[CH:9]=[CH:10][CH:11]=1>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:18])[NH:14][CH2:15][Cl:3])[CH:9]=[CH:10][CH:11]=1
Reactant: COCNC(=O)Oc1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NCCl)Oc1cccc(Cl)c1
Temperature: 0 °C
Yield: 70.1 %

Procedure:
62 ml (0.85 mole) of thionyl chloride were added to 167 g (0.775 mole) of N-methoxymethylcarbamic acid 3-chlorophenyl ester in 200 ml of carbon tetrachloride. After the evolution of gas had ceased, the mixture was cooled to 0° C, while keeping the reaction mixture stirrable by adding carbon tetrachloride. The precipitate which had separated out was filtered off, rinsed with cold carbon tetrachloride and dried in vacuo at 40° C. 119.5 g (70% of theory) of N-chloromethylcarbamic acid 3-chlorophenyl ester of melting point 90° C were obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:53][N:54]1[C:77]([CH3:79])([CH3:78])[CH2:76][C:57]2([NH:61][C:60](=[O:62])[N:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[C:58]2=[O:75])[CH2:56][C:55]1([CH3:81])[CH3:80])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:52])[CH2:23][N:24]3[C:47]([CH3:49])([CH3:48])[CH2:46][C:27]4([NH:31][C:30](=[O:32])[N:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]4=[O:45])[CH2:26][C:25]3([CH3:51])[CH3:50])=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.C(O[C:86](=[O:88])[CH3:87])(=O)C>C(OCC)(=O)C>[C:2]([O:52][CH:22]([CH2:23][N:24]1[C:25]([CH3:50])([CH3:51])[CH2:26][C:27]2([N:31]([C:86](=[O:88])[CH3:87])[C:30](=[O:32])[N:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:28]2=[O:45])[CH2:46][C:47]1([CH3:48])[CH3:49])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([O:1][C:17](=[O:20])[CH3:16])[CH2:53][N:54]3[C:55]([CH3:80])([CH3:81])[CH2:56][C:57]4([N:61]([C:5](=[O:4])[CH3:6])[C:60](=[O:62])[N:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[C:58]4=[O:75])[CH2:76][C:77]3([CH3:79])[CH3:78])=[CH:10][CH:9]=2)([CH3:13])[CH3:12])=[CH:19][CH:18]=1)(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COc3ccc(C(C)(C)c4ccc(OCC(O)CN5C(C)(C)CC6(CC5(C)C)NC(=O)N(CCCCCCCCCCCC)C6=O)cc4)cc3)C(C)(C)C2)C1=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN1C(=O)N(C(C)=O)C2(CC(C)(C)N(CC(COc3ccc(C(C)(C)c4ccc(OCC(CN5C(C)(C)CC6(CC5(C)C)C(=O)N(CCCCCCCCCCCC)C(=O)N6C(C)=O)OC(C)=O)cc4)cc3)OC(C)=O)C(C)(C)C2)C1=O

Procedure:
A mixture of 1.1 g of 2,2-bis{4-[2-hydroxy-3-(3-dodecyl-7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)propoxy]phenyl}propane and 10 g of acetic anhydride was refluxed for 48 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate and treated with an aqueous alkali. The solution was then dried and condensed by evaporation under reduced pressure, affording a viscous product which was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of ethyl acetate and n-hexane, giving the desired Compound No. 259 in the form of a white powder melting at 52°-55° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:36]=[CH:35][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])=[C:22]([F:37])[CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>C1COCC1.C(Cl)Cl>[C:38]([NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:36]=[CH:35][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:25])=[C:22]([F:37])[CH:21]=2)(=[O:18])=[O:19])[CH2:15][CH2:16]1)(=[O:41])[CH:39]=[CH2:40]
Reactant: NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)c(F)c2)CC1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.8 %

Procedure:
Diisopropylethylamine (0.51 ml, 3.0 mmol) was added in one portion to a stirred solution of 4-(4-Amino-piperidine-1-sulfonyl)-2-fluoro-N-phenethyl-benzamide (0.24 g, 0.6 mmol) in THF (10 ml), followed by the drop wise addition of acryloyl chloride (0.05 ml, 0.66 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 98% DCM, 2% Methanol) to give the title compound (0.06 g, 25% yield) as a white solid.
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1[NH:4]C=CN=1)=O.[CH:13]1([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][C:26]([O:28][C:29]4[N:34]=[CH:33][C:32]([C:35]([OH:37])=O)=[CH:31][CH:30]=4)=[CH:27][C:20]=3[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1.C1(N)CC1>ClCCl>[CH:13]1([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][C:26]([O:28][C:29]4[N:34]=[CH:33][C:32]([C:35]([NH:4][CH:3]5[CH2:1][CH2:8]5)=[O:37])=[CH:31][CH:30]=4)=[CH:27][C:20]=3[CH2:19][CH2:18]2)[CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: NC1CC1
Solvent: ClCCl
Product: O=C(NC1CC1)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonyl diimidazole (142 mg, 0.88 mmol) was added to a stirred solution of 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylic acid (E196b) (150 mg, 0.44 mmol) in dichloromethane (5 ml). After stirring at room temperature for 3 hours, cyclopropylamine (0.15 ml, 2.2 mmol) was added and the mixture was allowed to stir for a further 18 hours. The reaction mixture was applied to a SCX ion cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo to afford the title compound (E196). MS (ES+) m/e 378 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[CH:9]=[C:10]1[CH3:14]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(C)n(Cc3ccccc3Cl)c2c1
Yield: 44.7 %

Procedure:
A mixture of 6-methoxycarbonyl-2-methylindole (0.89 g), 2-chlorobenzyl bromide (1.45 g). potassium carbonate (0.780 g) and N,N-dimethylformamide (2 ml) is stirred at 80° C. for 18 hours. The solvent is evaporated away under reduced pressure, and the resulting residue is purified through silica gel column chromatography (eluent: hexane/chloroform=3/1) to obtain 1-(2-chlorobenzyl)-6-methoxycarbonyl-2-methylindole (30) (0.660 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[S:13](Cl)(Cl)(=[O:15])=[O:14]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:13]1(=[O:15])=[O:14]
Reactant: OCCNCc1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Product: O=S1(=O)OCCN1Cc1ccccc1Cl

Procedure:
contacting N-hydroxyethyl-2-chlorobenzylamine with sulfuryl chloride and an organic base to give N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine, and
Reaction SMILES: [Cl:1][C:2]([Cl:26])([Cl:25])[CH2:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](CC(O)=O)[CH:15]=1.SC1C=CC([C:32]([OH:34])=[O:33])=CC=1.ClC(Cl)(Cl)COC(=O)C1C=CC=CC=1CBr.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]([Cl:26])([Cl:25])[CH2:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:32]([OH:34])=[O:33])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1

Procedure:
The titled compound was prepared according to the method described for 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester above from 4-mercapto-benzoic acid (60 mg, 0.389 mmol), 2-bromomethyl-benzoic acid 2,2,2-trichloro-ethyl ester (135 mg, 0.389 mmol), cesium carbonate (152 mg, 0.467 mmol) and DMF (2 mL). The crude material (85 mg, 52%) was used for the next step without further purification; 1H NMR (400 MHz, CDCl3): δ 4.70 (s, 2H), 5.15 (s, 2H), 7.40 (d, 2H), 7.44-7.60 (m, 3H), 7.82 (d, 2H), 7.96 (d, 1H), 12.9 (br s, 1H); Mass spectrum: M−H+ 418.
Reaction SMILES: [I-:1].[Na+].[Li+].[Br-].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH2:21][NH:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1>>[I:1][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH2:21][NH:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: [I-]
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(I)c3c2)o1

Procedure:
The process was repeated as in Example 9 where 1.50 g of sodium iodide (NaI, 10 mmoles) were used instead of LiBr. 3.2 g of N-{[5-(4-iodoquinazoline-6-yl)furan-2-yl]methyl}-2-(methylsulfonyl)ethanamine of formula (VII, X═I) were obtained with a molar yield equivalent to 70%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[C:4]([N+:13]([O-])=O)[CH:3]=1.[BH4-].[Na+].O.C(OCC)(=O)C>C(Cl)Cl.CO.O.O.O.O.O.O.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[C:4]([NH2:13])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1-n1ccnc1
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(Br)ccc1-n1ccnc1
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
To a solution of 1-(4-bromo-2-nitro phenyl)-1H-imidazole (500 mg) in methylene chloride (10 mL) and methanol (10 mL) at 0° C. nickel hexahydrate (22.0 mg) and sodium borohydride (177 mg) were added one by one, and the reaction solution was agitated for 20 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ m NH; elution solvent:hexane:ethyl acetate=1:1→ethyl acetate), and 431 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH3:13][N:14]1[C:22]2[CH:21]3[CH2:23][CH:18]([CH2:19][CH2:20]3)[C:17]=2[C:16]([CH2:24]O)=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:13][N:14]1[C:22]2[CH:21]3[CH2:23][CH:18]([CH2:19][CH2:20]3)[C:17]=2[C:16]([CH2:24][O:1][N:2]2[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[N:15]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cn1nc(CO)c2c1C1CCC2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(CON2C(=O)c3ccccc3C2=O)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (4.10 g, 25.2 mmol), (1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)methanol 147 (2.24 g, 12.6 mmol) and triphenylphosphine (6.59 g, 25.2 mmol) in THF (100 mL) was added DIAD (5.35 mL, 27.6 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was subjected to chromatography to give 148 (1.80 g, 62%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.C([Li])CCC.CN(C)[CH:29]=[O:30]>O1CCCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:29]=[O:30])[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2cc(C=O)ccc2n1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (2.0 g, 5.83 mmol) was dissolved in 100 mL tetrahydrofurane. n-Butyllithium solution (1.6 M in hexane, 9.1 mL, 14.6 mmol) was slowly added at −78° C. The reaction mixture was allowed to warm to −10° C. and stirred at this temperature for 45 min. The reaction mixture was then cooled again to −78° C. and dimethylformamide (1.07 g, 14.6 mmol) was added. The mixture was then slowly warmed up and quenched with 200 mL water at 5° C. The solvent was evaporated off. The residue was extracted three times with ethyl acetate (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). 2-(2-Methoxy-benzylamino)-quinoline-6-carbaldehyde was obtained as a light yellow solid (683 mg, 40%), MS: m/e=293.1 (M+H+).