Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[NH2:24]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Cl)cc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzenesulfonyl chloride (1.74 mL, 13.57 mmol) and DIEA (0.34 mL, 2.49 mmol) were added to a solution of 3,5-dichloroaniline (2.0 g, 12.34 mmol) in DCM (50 mL). The resulting solution was stirred at room temperature for 48 h, during which a precipitate was formed. The reaction mixture was then evaporated to dryness and purified by flash column chromatography (ethyl acetate/hexanes=1/9) to give TC-IV-145 (1.90 g, 51%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:35][CH2:36][C:37]1[N:41]([C:42]2[S:43][C:44]([CH2:56][CH3:57])=[CH:45][C:46]=2[C:47](=[O:55])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[Cl:54])[C:40]([CH3:58])=[N:39][N:38]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[Cl:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[C:47]([C:46]1[CH:45]=[C:44]([CH2:56][CH3:57])[S:43][C:42]=1[N:41]1[C:40]([CH3:58])=[N:39][N:38]=[C:37]1[CH2:36][NH:35][C:10](=[O:12])/[CH:9]=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:55]
Reactant: O=C(O)/C=C/c1ccccc1O
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2O)s1
Yield: 17.8 %

Procedure:
Reaction was carried out in the same manner as in Example 186 using trans-3-(2-hydroxyphenyl)propenoic acid (1.64 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g), triethylamine (5.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g), and the obtained product was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as an eluent to give 0.90 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-hydroxyphenyl)propenamide. NMR (270 MHz, CDCl3):1.17(3H,t,J=7.6 Hz), 2.21(3H,s), 2.78(2H,q, J=7.6 Hz), 4.33(1H,dd,J=4.3 Hz,15.5 Hz), 4.51(1H,dd,J=6.3 Hz,15.5 Hz), 6.60(1H,d,J=16.8 Hz), 6.75-6.90(3H), 7.18(1H,m), 7.35-7.65(6H), 8.52(1H,m), 10.01(1H,s)
Reaction SMILES: [CH3:1][C:2]12[CH2:11][C:6]1([C:7]([O:9][CH3:10])=[O:8])[N:5]1[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:4]1[S:3]2.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[CH3:1][CH:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:5]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:4]2[S:3]1
Reactant: COC(=O)C12CC1(C)S[C@@H]1C(NC(=O)COc3ccccc3)C(=O)N12
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)C1=CC(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 4.4 h
Yield: 33.3 %

Procedure:
A solution of methyl 2-methyl-2,3-methylene-6-(2-phenoxyacetamido)-penam-3-carboxylate (2.1 g.) in dried dichloromethane (11 ml.) was dropwise added over 8 minutes at -10° C. to a solution of aluminum bromide (2.32 g.) in dried dichloromethane (23 ml.) and the reaction temperature was gradually elevated to room temperature, after which the mixture was stirred for 4.4 hours at room temperature. After the reaction, the reaction mixture was poured into ice-water (150 ml.) and the dichloromethane layer was separated, after which the aqueous layer was once extracted with chloroform. The combined dichloromethane and chloroform extract was washed in turn with water, 2% hydrochloric acid, water, a dilute sodium bicarbonate aqueous solution and water, and then dried over magnesium sulfate. After the solvent was distilled off, the obtained yellow oil was purified by column chromatography on silica gel (15 g.) using chloroform as developing solvent to give orange oil of methyl 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylate (0.7 g.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([O-:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([OH:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)OC)c1)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 25.6 %

Procedure:
Methyl (1RS, 2SR, 3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M, 1 ml ,1 mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5%AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>O>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CCCCI
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reaction time: 16 h

Procedure:
5-Amino-3-mercapto-4-phenoxybenzoic acid (5.22 g) is suspended in water (150 ml), 1 N sodium hydroxide is added until pH 8, and n-butyl iodide (7.4 g) is added to the resulting solution. The reaction mixture is stirred for 16 hours whereafter 5-amino-3-n-butylthio-4-phenxoybenzoic acid is precipitated by addition of 1 N hydrochloric acid until pH 2.5. After collection, recrystallization from aqueous ethanol, and drying in vacuo at 65°C, the compound is obtained with a melting point of 131°-132°C.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH2:5]([O:7][SiH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH3:6]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir].CC1C=CC(C)=CC=1>[Cl:4][CH2:1][CH2:2][CH2:3][Si:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCl
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: Cc1ccc(C)cc1
Solvent: C1=CCCC=CCC1
Product: CCO[Si](CCCCl)(OCC)OCC
Temperature: 80 °C
Yield: 83 %

Procedure:
In a minilab pressure reactor of the TINYCLAVE type (BUECHI) with a capacity of 25 ml, 4 g of p-xylene, 4.2 g (0. 055 mol) of allyl chloride and 8.2 g (0.05 mol) of triethoxysilane were mixed intensively with 0.16 mg (10-3 mol %) of chloro-(1,5-cyclooctadiene)iridium(I) dimer at room temperature for one hour. The reaction mixture was then heated at 80° C. for 2 hours in a thermostat. Analysis by gas chromatography gave a product yield of 83% of 3-chloropropyltriethoxysilane.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH3:27][S:28][C:29]1[N:36]2[C:32]([S:33][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:35]2)=[C:31]([S:50][CH3:51])[N:30]=1>>[CH3:27][S:28][C:29]1[N:36]2[C:32]([S:33][C:34]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:35]2)=[C:31]([S:50][CH3:51])[N:30]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(SC)c2s1
Product: CSc1nc(SC)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 61.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 762 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.10 g of 5,7-bis(methylthio)-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 720 mg of 4-nitrobenzyl (1S,5R,6S)-2-[5,7-bis(methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:42][CH2:43][C@@H:44]([C:46]1[CH:47]=[CH:48][C:49]([OH:57])=[C:50]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:51]=1)[OH:45].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[OH:57][C:49]1[CH:48]=[CH:47][C:46]([C@@H:44]([OH:45])[CH2:43][NH:42][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:19][CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:22]=4)[CH2:14][CH2:13]3)=[CH:9][CH:10]=2)=[CH:51][C:50]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54]
Reactant: COC(Cc1ccc(NC2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1)OC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
N-[4-(2,2-Dimethoxyethyl)phenyl]-1-(4-phenyl-1,3-thiazol-2-yl)-4-piperidinamine (0.415 g, 30 0.98 mmol) was added to a pre-prepared mixture of sodium iodide (0.367 g, 2.45 mmol) and trichloro(methyl)silane (0.229 mL, 1.95 mmol) in anhydrous acetonitrile (70 mL). The reaction was stirred at ambient temperature for 10 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and the solvent partially removed in vacuo. The aldehyde solution was used directly and treated with methanol, acetic acid (0.088 mL, 1.47 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.241 g, 0.98 mmol) followed by sodium cyanoborohydride (0.067 g, 0.97 mmol). The reaction was stirred at ambient temperature overnight. The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to yield the title compound (0.092 mmol, 0.151 mmol).
Reaction SMILES: C(=O)=O.CC(C)=O.[Li]CCCC.Br[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>CC(OC)(C)C>[F:20][C:17]1[N:18]=[CH:19][C:14]([B:25]([OH:26])[OH:24])=[CH:15][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cn1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: OB(O)c1ccc(F)nc1
Temperature: 6 °C
Reaction time: 0.83 h
Yield: 79 %

Procedure:
To stirred and cooled (dry ice-acetone bath) anhydrous [TBME] (620 mL; in a 3 L three-necked round-bottomed flask equipped with mechanical stirrer, temperature probe with adapter, and nitrogen inlet) was added (via syringe) 2 M BuLi (352 mL, 0.704 mol, 1.2 eq). To this rapidly stirred and cooled (<−75° C.) mixture was added a solution of 3 (102.2 g, 0.581 mol) in anhydrous TBME (100 mL) over a period of 13 min during which time the internal temperature rose to −62° C. The reaction was stirred for another 45 min (the temperature was maintained between −62° C. and −80° C.), followed by the rapid and sequential addition of four portions of triisopropylborate (total of 180 g, 0.957 mol, 1.65 eq). At the end of the addition the internal temperature had risen to −33° C. After stirring an additional 45 min over the cold bath (internal temperature lowered from −33° C. to −65° C.), the cold bath was removed and the stirred mixture on its own rose to −22° C. over a period of 50 min. After warming (via water bath) to 6° C. over a period of 15 min, the stirred reaction mixture was placed in an ice-water bath and then quenched under nitrogen with a cooled solution of NaOH (160 g) in water (500 mL). Once the addition was complete, the internal temperature was 20° C. This mixture was stirred at room temperature for 1.5 h. The aqueous layer was removed, neutralized to pH 7 with ˜350 mL concentrated HCl, and then extracted with EtOAc (3×1 L). Because the pH was now 8-9, the aqueous layer was adjusted to pH 7 using 15 mL concentrated HCl and extracted further (2×1 L) with ethyl acetate. The combined EtOAc extracts were dried (Na2SO4), filtered, and concentrated to a volume of ˜150 mL. With swirling of the concentrate, heptane was added in portions (total volume of 300 mL) resulting in the precipitation/crystallization of the product. Filtration, washing of the solid with heptane (100 mL, 300 mL, then another 300 mL), and air drying gave the title product as an off-white solid (68.6 g, yield of 79-90%*; LC purity of 96.4%, NMR showed an estimated 5.5% w/w of heptane), which was used successfully without further purification. LC/MS showed it to be a mixture of the two following entities, the intensity of the higher molecular weight entity being major (*Note: yield of reaction is 79% if the boronic acid is assumed to be the only constituent and is 90% if it is assumed that the cyclic borate is the only constituent):
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C1C=C(Br)C=C(C(F)(F)F)C=1.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([CH3:43])[CH:41]=2)[N:36]=[C:35]([CH3:44])[CH:34]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[CH3:44][C:35]1[CH:34]=[C:33]([C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([CH3:43])[CH:41]=2)[N:36]=1
Reactant: Cc1ccc2nc(C)cc(Cl)c2c1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2nc(C)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2c1

Procedure:
First, 3,5-bis(trifluoromethyl)phenylmagnesium bromide prepared from Mg and 3,5-bis(trifluoromethyl)bromobenzene was dropped into a THF solution of 4-chloro-2,6-dimethylquinoline (1 g) andNi(dpp)Cl2 (dpp: 1,3-bis(diphenylphosphino)propane) (0.1 g). Reactions were allowed to take place for 24 hours at room temperature. Water was added to the reaction solution and the organic layer was extracted using CHCl3. The solvent was removed under reduced pressure and the residue was purified through column chromatography to obtain 2,6-dimethyl-4-[3,5-bis(trifluoromethyl)phenyl]quinoline (0.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[C:20]([CH3:33])=[CH:19][N:18]=3)=[C:9]([O:34][CH3:35])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:36][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:34][CH3:35])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[C:20]([CH3:33])=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Yield: 68.6 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 115, 210 mg, 0.43 mmol), iron (144 mg, 2.58 mmol) and NH4Cl (16.13 mg, 0.30 mmol) in ethanol (6 mL) and water (2 mL) were heated at reflux for 2 h. The crude mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave a brown foam after concentration of appropriate fractions in vacuo. Further purification by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia provided material that was concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% CH3OH in CH2Cl2 gave the title compound (135 mg, 69%) as a brown foam; 1H NMR: 2.11 (6H, s), 2.35 (3H, s), 3.04 (1H, p), 3.44 (2H, t), 3.89 (3H, s), 3.92 (2H, s), 3.9-3.97 (2H, m), 6.28 (1H, s), 7.12 (1H, dd), 7.2-7.26 (1H, m), 7.28 (1H, s), 7.48 (1H, d), 7.55 (1H, s), 8.00 (1H, s), 8.15 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 458.31.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 4 h
Yield: 65.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.14 mL) was added to a solution of [5-(4-{1-ethyl-1-[4-(1-hydroxy-cyclohexylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 99-(2); 24.4 mg, 0.0465 mmol) in methanol (1.0 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (5% methanol/dichloromethane) to give the title compound (15.5 mg, 65%).
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.C1([Li])C=CC=CC=1.[C:24](=[O:26])=[O:25].Cl>O1CCCC1.O>[Br:7][C:5]1[N:6]=[C:2]([C:24]([OH:26])=[O:25])[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Br:8]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C(=O)O)nc(Br)c1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4,5-tribromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (5.0 g, 11.5 mmol) in tetrahydrofuran (200 ml) at −78° C. is added phenyl lithium (7.0 ml, 12.6 mmol, 1.8 M in THF). After 30 minutes stirring at −78° C. CO2-pellets (˜3.0 g) are added. The mixture is allowed to warm to room temperature, water is added, and the pH is carefully adjusted with 6N HCl (aqueous) to pH=5. The mixture is extracted with ethyl acetate (2×50 ml) and the combined organic layer is washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude 4,5-dibromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid is obtained as a yellow oil, and used without further purification 4.2 g, 91%, LC/MS ESI m/z (M−H)−398.8.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:12]([NH2:13])=[CH:11][C:10]([CH2:14][S:15](/[CH:18]=[CH:19]/[C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([O:28][CH3:29])=[CH:22][C:21]=2[O:30][CH3:31])(=[O:17])=[O:16])=[CH:9][N:8]=1>N1C=CC=CC=1>[CH3:5][O:6][C:7]1[C:12]([NH:13][C:1](=[O:3])[CH3:2])=[CH:11][C:10]([CH2:14][S:15](/[CH:18]=[CH:19]/[C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([O:28][CH3:29])=[CH:22][C:21]=2[O:30][CH3:31])(=[O:17])=[O:16])=[CH:9][N:8]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NC(C)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Acetyl chloride (0.054 mL, 0.76 mmol) was added dropwise into the solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (80 mg, 0.21 mmol) in dry pyridine (5 mL) on an ice bath. The mixture was warmed to room temperature and stirred overnight. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:3 v/v) to afford pure product as a white solid (38 mg, 44%). 1H-NMR (CDCl3-d6): δ 2.21 (s, 3H, CH3), 3.86 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.21 (s, 2H, CH2), 6.11 (s, 2H, Ph-H), 7.13 (d, 1H, J=15.6 Hz, CH), 7.61 (s, 1H, NH), 7.88 (d, 1H, J=15.6 Hz, CH), 7.89 (d, 1H, J=2.0 Hz, Py-H), 8.65 (d, 1H, J=2.0 Hz, Py-H); HR-MS (ESI+) m/z 437.1460 [M+H]+ C20H24N2O7S requires 436.1304,
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].CN(C)C=O.[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:31]=[C:32]([C:33]#[N:34])[C:15]=2[N:14]=1>O>[CH3:12][C:13]1[N:17]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:29]=[C:30]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:31]=[C:32]([C:33]3[NH:34][N:3]=[N:2][N:1]=3)[C:15]=2[N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(-c3nnn[nH]3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Yield: 13 %

Procedure:
In a two 5 mL MW vial was added in 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile, prepared as described in Example 24 (80 mg, 0.209 mmol), sodium azide (109 mg, 1.673 mmol) and ammonium chloride (90 mg, 1.673 mmol) and N,N-Dimethylformamide (DMF) (2 mL). The reaction mixture was subjected to MW irradiation for 15 min at 180° C., then 80 min at 185° C. LC-MS analysis only showed 30% conversion; however, heating for longer time caused the decomposition of the product. The two reaction mixtures were combined. The combined mixture was added in water (10 mL) and extracted with DCM (30 mL×4). The combined organic phases were washed with saturated NH4Cl solution, dried, and concentrated. The reaction was subjected to purification on a silica column (20˜60% EtOAc/Hexane) and then (1˜5% MeOH/DCM) to give the product (24 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 3.08-3.15 (m, 4H) 3.68-3.75 (m, 4H) 6.10 (s, 2H) 6.40 (d, J=7.33 Hz, 1H) 7.26-7.39 (m, 2H) 7.56-7.74 (m, 3H) 7.88 (d, J=8.34 Hz, 1H) 8.03 (d, J=8.08 Hz, 1H) 8.26 (d, 1 H). MS(ES+) m/e 426.0 [M+H]+.