Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[N+:47]([C:50]1[CH:61]=[CH:60][C:53]([CH2:54][O:55][C:56](=[O:59])[CH2:57][NH2:58])=[CH:52][CH:51]=1)([O-:49])=[O:48].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[N+:47]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][O:55][C:56]([CH2:57][NH:58][C:1]([C:4]2[N:5]=[C:6]([N:9]3[CH2:10][CH:11]([S:13][C:14]4[C@H:15]([CH3:45])[C@@H:16]5[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:12]3)[S:7][CH:8]=2)=[O:3])=[O:59])=[CH:60][CH:61]=1)([O-:49])=[O:48]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Reactant: NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Subsequently, to a suspension of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (207.4 mg, 0.31 mmol) (obtained as described in Reference Example 41(7)) and glycine p-nitrobenzyl ester hydrochloride (116 mg, 0.47 mmol) (obtained as described above) in dimethylformamide (10.5 ml) were added diethylphosphoryl cyanide (0.072 ml, 0.47 mmol) and triethylamine (0.14 ml, 1.00 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with a 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(p-nitrobenzyloxycarbonylmethyl)carbamoyl-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (209.7 mg, yield 77%) as a pale yellow syrup.
Reaction SMILES: [CH:1]([CH:4]1[C:10]2=[C:11]3[C:15](=[CH:16][CH:17]=[C:9]2[O:8][CH2:7][CH2:6][NH:5]1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]3)([CH3:3])[CH3:2].C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:1]([CH:4]1[C:10]2=[C:11]3[C:15](=[CH:16][CH:17]=[C:9]2[O:8][CH2:7][CH2:6][N:5]1[CH3:29])[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]3)([CH3:3])[CH3:2]
Reactant: CC(C)C1NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)C1c2c(ccc3c2ccn3S(=O)(=O)c2ccccc2)OCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
1-Isopropyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 93, 25 mg, 0.068 mmol) was dissolved in methanol (4 mL) and formaldehyde (37 wt. % in H2O, 0.090 mL, 1.1 mmol) was added followed by sodium triacetoxyborohydride (72 mg, 0.34 mmol). The reaction mixture was allowed to stir at room temperature overnight, evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1.4 mg). MS m/z 385 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27]N(C=O)C>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18](=[O:20])[C:7]3[C:5](=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[CH:8]=3)[O:6][CH:27]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.87 g, 6 mmol), 4-bromophenyl acetic acid (1.29 g, 6 mmol), BF3Et2O (4 ml), PCl5 (1.9 g, 9.1 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one a flakey white solid (1.2 g, 56.8%); Rf 0.81 ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]2[CH:16]=[N:17][S:18][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.CCN(C(C)C)C(C)C.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[S:18][N:17]=[CH:16][C:15]=2[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:32]
Reactant: O=C(O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 4-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-5-carboxylic acid (240 mg, 0.58 mmol) in THF (6 mL) was added DIPEA (396 μL, 2.34 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (119 mg, 1.15 mmol), HOBt (156 mg, 1.15 mmol) and EDCI (221 mg, 1.15 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between ethyl acetate and water. The organic extract was washed with aqueous saturated sodium bicarbonate solution then water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound (258 mg, 89%). LCMS (Method B): RT=3.83 min, [M+H]+=500.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-benzyloxy-3-hydroxybenzaldehyde (5 g, 21.9 mmol) in DMF (50 mL) was added cyclopentyl bromide (4.7 mL, 43.8 mmol) and K2CO3 (12.1 g, 87.6 mmol). The reaction mixture was stirred at r.t. overnight. K2CO3 was then filtered from the mixture. The mixture was extracted with EtOAc, and the organic layer was washed with water (2×) and then brine, and finally dried over Na2SO4. The product was concentrated under reduced pressure and purified by silica gel to provide a colorless oil which solidified to a white solid upon standing. Yield: 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10](O)C>[Pd]>[OH:9][C:4]1[CH:3]=[C:2]2[C:7]([CH:8]=[CH:10][NH:1]2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(O)cc1N
Reactant: CCO
Agent: [Pd]
Product: Oc1ccc2cc[nH]c2c1
Yield: 38 %

Procedure:
The semicarbazone obtained above was reduced catalytically using 10% palladium on carbon in ethanol to yield a mixture of 6-hydroxyindole 38% yield, mp 124°-6° C., and 3-amino-4-methylphenol which were separated by column chromatography.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][CH2:6][C:7]([OH:9])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:5][CH2:6][C:7]([O:3][CH2:2][CH2:1][O:4][C:7](=[O:9])[CH2:6][Cl:5])=[O:9]
Reactant: O=C(O)CCl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCl)OCCOC(=O)CCl
Temperature: 25 °C
Yield: 69.9 %

Procedure:
In a 2 liter, 4 necked round bottom flask equipped with a mechanical stirrer, a solution of ethylene glycol (100 grams, 1.611 moles), chloroacetic acid (385 grams, 4.031 moles) and para toluenesulphonic acid (1 gram) in toluene (750 ml), was refluxed for 8 hours using a Dean-Stark apparatus. It was then cooled to room temperature. The toluene layer was washed with water (2×300 ml), 5% sodium bicarbonate solution (3×500 ml) and again with water (2×300 ml), dried over sodium sulfate, and distilled to provide crude 1, which was purified by high vacuum distillation to provide pure 1 (242 grams, 69.8%), which slowly crystallized to white crystals. m.p: 44° C., 1H NMR (CDCl3) δ 4.16 (s, 2H, CH2), 4.85 (s, 2H, CH2)
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:20].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>C(Cl)(Cl)Cl>[C:37]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:20])(=[O:39])[CH3:38]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc(N)c(N(C)Cc2ccc(Cl)cc2Cl)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c(N(C)Cc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-amino-3-((N-methyl)-2,4-dichlorobenzylamino)-(N-(n-pentanesulfonyl))benzamide was dissolved in chloroform, and triethylamine and acetyl chloride were added to the solution. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with water and separated into aqueous and organic layers. The organic layer was washed with water and concentrated. The resulting residue was crystallized from ether. The crystals were filtrated and dried to yield 4-(acetylamino)-3-((N-methyl)-2,4-dichlorobenzylamino)-(N-(n-pentanesulfonyl))benzamide (33).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(CCc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[2-(N-methylpiperazino)-ethyl]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: O=[N:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[N:14]#[C:15][NH2:16]>>[NH2:16][C:15]1[NH:2][CH:3]=[C:4]([C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[N:14]=1
Reactant: O=NCCc1c[nH]c2ccccc12
Reactant: N#CN
Product: Nc1nc(-c2c[nH]c3ccccc23)c[nH]1

Procedure:
In another embodiment of the invention, a method of synthesizing N,N-didesmethylgrossularine-1 2 is described comprising: condensing oxotryptamine 3 and cyanamide in the absence of air to produce 2-amino-4-(3-indolyl)imidazole 6; exposing 2-amino-4-(3-indolyl)imidazole 6 to an ammonia saturated methanol solution in air to produce imine 10; and exposing imine 10 to hydrolosis conditions to produce N,N-didesmethylgrossularine-1 2.
Reaction SMILES: [CH2:1]([CH:3]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:23])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:39][C:40]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[C:41]=1[C:42](Cl)=[O:43]>ClC1C=CC=CC=1>[CH2:1]([CH:3]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:22](=[O:23])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:42]([C:41]1[C:40]([CH3:39])=[CH:48][C:47]([CH3:49])=[CH:46][C:45]=1[CH3:50])=[O:43])[CH:10]=2)[CH3:2]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CCCCC(CC)Cn1c2ccccc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCCCC(CC)Cn1c2ccc(C(=O)c3c(C)cc(C)cc3C)cc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Temperature: 65 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To [11-(2-ethylhexyl)-11H-benzo[a]carbazol-5-yl]-(4-fluorophenyl)-methanone (2.00 g, 4.43 mmol) in chlorobenzene (12 mL) are added AlCl3 (1.24 g, 9.30 mmol) and 2,4,6-trimethylbenzoyl chloride (0.85 g, 4.65 mmol) at 0° C. After stirring for 2 hours at 65° C., the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of CH2Cl2 and n-hexane (4:1) to obtain a yellow solid (1.39 g, 52%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.83 (t), 0.92 (t), 1.19-1.47 (m), 2.13 (s), 2.26-2.35 (m), 2.35 (s), 4.74-4.78 (m), 6.93 (s), 7.16 (t), 7.56-7.59 (m), 7.67 (t), 7.93-7.98 (m), 8.28 (s), 8.36 (d), 8.55 (br), 8.62 (d); 19F-NMR spectrum (CDCl3). δ [ppm] −105.13.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][N:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:41][C:38]3[CH:37]=[N:36][C:35]([Br:34])=[CH:40][CH:39]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: BrCc1ccc(Br)nc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3ccc(Br)nc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 77.9 %

Procedure:
Using 1.4 g (3.1 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 2-bromo-5-bromomethyl-pyridine (0.77 g, 3.1 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.40 (9H, s), 1.80 (4H, m), 3.2 (1H, m), 3.70 (1H, m), 5.25 (2H, s), 6.75 (1H, d), 7.0 (1H, s), 7.15 (2H, d), 7.22 (1H, s), 7.45 (1H, s), 7.7 (1H, d), 7.85 (3H, m), 8.3 (1H, d), 8.5 (1H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[ClH:27]>O>[ClH:27].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CCCOCCCCCBr)cc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: COc1ccc(CCCOCCCCCNCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
1-[3-[(5-Bromopentyl)oxy]propyl]-4-methoxybenzene (2.0 g) was added to benzylamine (6 ml) at 120° under nitrogen. The solution was stirred for 2 h at 120° then added (hot) to 2N hydrochloric acid (50 ml) and water (25 ml). The resulting precipitate was collected by filtration, washed with 2N hydrochloric acid, water and ER then dried at 50° under vacuum to give the title compound as a white solid (1.79 g) m.p. 118°-121°.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][NH:46][CH3:47]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][N:46]([CH3:47])[CH3:45])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CNC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN(C)C)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 65 °C
Yield: 20 %

Procedure:
To a pressure tube was added the product of Example 145 (150 mg, 0.23 mmol), tetra-n-butylammonium iodide (85 mg, 0.23 mmol), and 2.0 M solution of dimethylamine in THF (6 mL). The tube was sealed and heated at 65° C. for 14 h. The solution was cooled and concentrated under reduced pressure, and the crude material was purified by chromatography (silica gel, 0–20% MeOH/DCM) to provide the title compound (30 mg, 20%). 1H-NMR (CDCl3): δ 8.83 (1H, s), 7.45 (2H, d), 7.22–7.34 (5H, m), 7.11 (1H, dd), 6.71 (1H, dd), 6.63 (1H, d), 6.52 (1H, d), 5.14 (2H, s), 4.12 (2H, t), 3.70 (3H, s), 3.04 (2H, s), 2.97 (2H, q), 2.82 (2H, t), 2.40 (6H, s), 2.35 (6H, s), 1.02 (3H, t); MS(ESI): 660(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[CH:7]=1)=[O:5])[CH3:2].S(OCC)(O[CH2:18][CH3:19])(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH2:18][CH3:19])[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Product: CCCc1cc(C(=O)OCC)n(CC)n1

Procedure:
This pyrazole was prepared from 3-n-propylpyrazole-5-carboxylic acid ethyl ester and diethyl sulphate, following the procedure described in Example 1, and was obtained as a colourless oil (72%). Rf 0.5 (silica; ethyl acetate, hexane; 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:11](Cl)=[O:12])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>C1C=CC=CC=1>[CH2:20]([NH:23][C:11]([CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH2:7]1)=[O:12])[CH2:21][CH3:22]
Reactant: CCCN
Reactant: O=C(Cl)C1CCc2cc(C3CCCCC3)c(Cl)cc21
Solvent: c1ccccc1
Product: CCCNC(=O)C1CCc2cc(C3CCCCC3)c(Cl)cc21

Procedure:
In 35 ml. of benzene is dissolved 2.97 g. of 6-chloro-5-cyclohexylindan-1-carbonyl chloride and to the solution is added 1.77 g. of n-propylamine under cooling and with stirring. The mixture is stirred at room temperature for 1 hour, after which time it is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residual crystals are recrystallized from acetone. The procedure yields N-propyl-6-chloro-5-cyclohexylindan-1-carboxamide, Melting poing: 140.5 - 142.5° C.
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[ClH:1].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: N=c1ccn(-c2ccccc2)nc1
Agent: Cl
Product: CC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 74 %

Procedure:
15.0 g (72.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 100 ml of acetic anhydride were heated at 100° C. for 2 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from ethanol. 13.3 g (74% of theory) of 4-acetylimino-1,4-dihydro-1-phenylpyridazine hydrochloride were isolated as colorless crystals of melting point 257°-260° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].CCN(C(C)C)C(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][C:28]2[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=2)=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][C:28]2[S:32][C:31]([S:33](=[O:35])(=[O:34])[NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])=[CH:30][CH:29]=2)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reactant: CC(C)(CN)CO
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2 equivalents of 3-Amino-2,2-dimethyl-propan-1-ol (1.0 g, 10 mmol) in DMF in the presence of 2 equivalents of DIEA (1.7 ml, 10 mMol) is added a solution of sulfonylchloride (1b) (1.75 g, 5 mMol, 1 equivalent) in DMF. The reaction mixture is stirred for 12 h at room temperature. DCM is added and any excess of amine is extracted into 0.1N HCl solution. The organic phase is washed with brine and dried over MgSO4. 4-Chloro-N-[5-(3-hydroxy-2,2-dimethyl-propylsulfamoyl)-thiophen-2-ylmethyl]-benzamide (compound of formula XII) is obtained after evaporation of the solvent. LC-MS analysis and NMR analysis showed that the compound was pure enough to carry on the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9].C([Li])CCC.[CH2:16]=[O:17].O>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]([CH2:16][OH:17])=[CH:7][C:8]=1[CH3:9])[CH3:10]
Reactant: C=O
Reactant: Cc1ccoc1CN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(CO)oc1CN(C)C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of N,N,3-trimethyl-2-furanmethanamine (10.3 g) in dry tetrahydrofuran (200 ml) under nitrogen was treated over 2 hr with 1.6 M n-butyl lithium in hexane 846.2 ml) at -40° to -45° C. After stirring for 2 hr at room temperature paraformaldehyde (2.3 g) in dry tetrahydrofuran (100 ml) was added and the solution stirred overnight. Water (10 ml) was added and the solvent evaporated. Ethyl acetate (200 ml) and sodium sulphate were added and the organic phase was evaporated giving an oily residue which was distilled (85°/0.1 mm) affording the title compound (8 g).