Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:15]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:15])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
A solution of 21 g of 3-(4-nitrophenyl)propionyl chloride in 30 ml of chloroform was added dropwise into a mixture of 75 ml of concentrated aqueous ammonia and 75 ml of ice water. The resultant mixture was then stirred for 2 hours under ice-cooling. The resultant precipitate was collected by filtration, dried in air and recrystallized from ethyl acetate, thereby obtaining 13.7 g of 3-(4-nitrophenyl)propanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(=O)(=O)(O)[OH:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:17])=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=S(=O)(O)O
Reactant: N#CC1(N2C(=O)c3cccc(Cl)c3C2=O)CCCCC1
Solvent: ClCCl
Product: NC(=O)C1(N2C(=O)c3cccc(Cl)c3C2=O)CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution containing 300 mgs. 3-chloro-N-(1-cyanocyclohexyl)-phthalimide in 3 ml. methylene chloride is added, with good stirring, 0.38 ml. concentrated sulfuric acid. After 0.5 hour, ice is added and the aqueous phase extracted with chloroform. The organic phase is washed with water, dried and evaporated to give the 1-(3-chlorophthalimido)cyclohexanecarboxamide which can be purified by recrystallization from aqueous ethanol, m.p. 193°-194° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl.C(OCC)(=O)C>[Cl:24][CH2:25][C:26]([NH:18][NH:17][C:15]([C:14]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])=[C:10]([Cl:22])[C:11]2[N:12]([CH:19]=[CH:20][N:21]=2)[CH:13]=1)=[O:16])=[O:27]
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCl)NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (100 mg, 0.25 mmol) of Step A, Example 35 was suspended in dichloromethane (2 mL) and 4-Me morpholine (0.040 mL, 0.36 mmol) was added. The mixture was cooled to 0° C. and then chloroacetyl chloride (0.029 mL, 0.36 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour under N2. Rinsed reaction mixture into a separatory funnel with a small amount of tetrahydrofuran and methanol and then diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (20:1 dichloromethane/methanol) to yield the desired product (64 mg, 54%) as a yellow solid. MS ESI (+) m/z 474, 476 (M+, Cl, Br pattern) detected.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][C:6]3([OH:14])[CH2:7][C:8]([OH:13])([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:15]([NH:22][C:23]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[C:18]([O:17][C:15](=[O:16])[NH:22][C:23]1([CH2:28][NH:2][CH:3]2[CH:10]3[CH2:9][C:8]4([OH:13])[CH2:7][C:6]([OH:14])([CH2:5][CH:4]2[CH2:12]4)[CH2:11]3)[CH2:24][CH2:25][CH2:26][CH2:27]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: NC1C2CC3(O)CC1CC(O)(C2)C3
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(CNC2C3CC4(O)CC2CC(O)(C3)C4)CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of 6-amino-adamantane-1,3-diol hydrochloride (258 mg, J. Med. Chem. 50, 2007, 149), N-Boc-cycloleucinal (250 mg) and acetic acid (0.67 ml) in MeOH (5.0 ml), sodium triacetoxyborohydride was added at room temperature. The mixture was stirred at 60° C. for 30 min. The mixture was basified with saturated NaHCO3 solution. The mixture was extracted with AcOEt, washed with brine, dried over MgSO4 and evaporated. The residue was purified with silica gel chromatography (CH2Cl2:MeOH:NH4OH=from 100:0:0 to 90:9:1) to obtain the title compound (250 mg, 56%) as a white amorphous.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:33][CH2:34][C:35]([NH:37]O)=[NH:36].C1C2C(C3ON=C(N)N=3)CN(C2)C1>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]2[O:6][N:37]=[C:35]([CH2:34][Cl:33])[N:36]=2)[CH:7]=1
Reactant: N=C(CCl)NO
Reactant: O=C(O)c1cc(Cl)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Nc1noc(C2CN3CCC2C3)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)cc1-c1nc(CCl)no1
Yield: 56.3 %

Procedure:
The acyclic intermediate was prepared from 2-fluoro-5-chlorobenzoic acid (550 mg, 3.15 mmol), EDCI (665 mg, 3.47 mmol), HOBT (469 mg, 3.47 mmol) and 2-chloro-N-hydroxy-acetamidine (377 mg, 3.47 mmol) in DMF (10 mL). To effect cyclization to oxadiazole, DMF (15 mL) was added to the intermediate residue and the mixture was heated for 1 hour. The product was purified by flash column chromatography using 10% ethyl acetate in hexane afforded the title compound (438 mg, 56% yield over 2 steps, white solid). 1H NMR (CDCl3) δ (ppm): 8.16 (m, 1H), 7.58 (m, 1H), 7.29 (m, 1H), 4.72 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=1.[Br:23]N1C(=O)CCC1=O>CC(C)=O>[Br:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Solvent: CC(C)=O
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
22 mg 4-(1H-Indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one is suspended in 30 mL acetone and 2 mg N-bromosuccinimide is added. The reaction mixture is stirred for 3 hours at room temperature, the precipitated product isolated by filtration and washed with acetone. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (0.05% HCOOH). Yield 11.2 mg. LC-MS (ES+) 368 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2([C:19]#[N:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([S:7]([C:10]2([CH2:19][NH2:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Yield: 16.7 %

Procedure:
Similarly to Example 1(b), by reaction of 1 g (3.5 mmol) of 2-benzenesulfonyl-indane-2-carbonitrile with 161 mg (4.2 mmol) of lithium aluminum hydride. 168 mg of C-(2-benzenesulfonyl-indan-2-yl)-methylamine is obtained in the form of a brown oil. (Yield=17%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:34])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.O[C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:34][C:16]([F:15])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([O:32][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
DIAD (2.262 mL, 11.49 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (3 g, 10.44 mmol), ethyl 4-hydroxybenzoate (1.909 g, 11.49 mmol) and triphenylphosphine (3.01 g, 11.49 mmol) in THF (50 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol. The crude solid was triturated with MeOH to give a solid which was collected by filtration and dried under vacuum to give ethyl 4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzoate (2.220 g, 49%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])=[C:12]2[CH:11]=[N:10]1.C([O-])(=O)C.[Na+].CC(C)(O)[C:53]#[N:54].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(C(C)C)CC)(C)C.C(OC)(C)(C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:53]#[N:54])[C:3]=1[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])[C:12]=2[CH:11]=[N:10]1
Reactant: CC(C)(O)C#N
Reactant: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Br)cn1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)cn1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A solution of (2S)-2-(1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate BO1) (1 equiv) in inerted* DMF (5 rel vols) and diisopropylethylamine (DIPEA) (1.25 equivs) was kept in an inert atmosphere and was added with stirring to an inerted* mixture of tris(dibenzylideneacetone)dipalladium(0) (0.025 equivs), sodium acetate (0.1 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.075 equivs) in DMF (5 rel vols) at 90° C. over 5 minutes. The mixture was stirred for 10 minutes and then an inerted* solution of acetone cyanohydrin (1.4 equivs) in DMF (2 rel vols) was added over 20 hours with stirring. When the reaction was completed the mixture was cooled to 5° C. and diluted with methyl tert-butyl ether (7 rel vols) and then sodium bicarbonate (0.3 equivs) in water (2.5 rel vols). The organic phase was separated and the aqueous phase washed with methyl tert-butyl ether. The combined organic extract and organic washings were evaporated under reduced pressure at 35° C. and the residue was purified by chromatography. Yield 74%. *Nitrogen bubbled through before use.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[CH3:18][C:19]1([CH3:37])[C:31]2[CH:30]=[C:29](O)[C:28]3[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=3[C:26]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]1=2>>[C:12]1([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:11][C:29]3[C:28]4[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=4[C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]([CH3:37])([CH3:18])[C:31]=4[C:30]=3[CH:10]=[CH:9]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#CC(O)(c1ccccc1)c1ccc(F)cc1
Reactant: CC1(C)c2ccccc2-c2c1cc(O)c1ccccc21
Product: CC1(C)c2ccccc2-c2c1c1c(c3ccccc23)OC(c2ccccc2)(c2ccc(F)cc2)C=C1

Procedure:
The process from Step 3 of Example 1 was followed except that 1-(4-fluorophenyl)-1-phenyl-2-propyn-1-ol (from Step 1) was used instead of 1-ferrocenyl-1-(4-fluorophenyl)-2-propyn-1-ol. The 1-(4-fluorophenyl)-1-phenyl-2-propyn-1-ol was reacted with 7,7-dimethyl-7H-benzo[C]fluoren-5-ol (from Step 3 of Example 1) to provide 3-phenyl-3-(4-fluorophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran. Mass spectrometry analysis supported a molecular weight consistent with 3-phenyl-3-(4-fluorophenyl)-13,13-dimethyl-3H,13H-indeno[2′,3′:3,4]naphtho[1,2-b]pyran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 55.4 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 300 mg of 5- bromoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 144 mg of the target compound.
Reaction SMILES: [F:1][C:2]1C=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH3:10][O:11][C:12]([O:15][CH3:16])(C)[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:10][O:11][CH:12]([O:15][CH3:16])[C:13]1[CH:8]=[CH:7][CH:6]=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccccc1F
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(OC)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 12.2 g of 2-fluorobenzaldehyde, 15 ml of 2,2-dimethoxypropane and 0.1 g of 4-toluenesulphonic acid was stirred at room temperature. After 24 hours, diethyl ether was added and the resultant solution washed with saturated sodium bicarbonate solution. Drying and evaporation of the organic phase gave the crude acetal. Distillation under vacuum at 90°-95° C./0.08 mm yielded the title compound as a colourless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:25]([O-:28])(=O)=[O:26])[CH:8]=[CH:9][C:10]=1[N:11]=[N:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[CH:15][C:14]=1[NH:21][C:22](=[O:24])[CH3:23])(=[O:4])=[O:3].[Ca+2].CS(C1C=C(S([O-])(=O)=O)C=CC=1N=NC1C=C([Cl:48])C(O)=CC=1NC(=O)C)(=O)=O.CC(N(C)C)=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:22]([NH:21][C:14]1[C:13]([N:12]=[N:11][C:10]2[CH:9]=[CH:8][C:7]([S:25]([Cl:48])(=[O:28])=[O:26])=[CH:6][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]([Cl:19])=[C:16]([OH:20])[CH:15]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1N=Nc1ccc(S(=O)(=O)[O-])cc1S(C)(=O)=O
Agent: [Ca+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC(=O)Nc1cc(O)c(Cl)cc1N=Nc1ccc(S(=O)(=O)Cl)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 18 g of calcium 3-methylsulfonyl-4-(2-acetylamino-5-chloro-4-hydroxyphenylazo)phenylsulfonate, 25 ml of dimethylacetamide, and 54 ml of acetonitrile was added dropwise to 18 ml of phosphorus oxychloride at room temperature with stirring. After completion of the addition, the reaction was allowed to proceed at 60° C. for 3 hours, and the reaction mixture was cooled to room temperature and then poured in 1 l of ice water. The mixture was stirred at a temperature of 10° C. or less for 1 hour and the resulting crystalline precipitate was collected by filtration, washed with water and air-dried.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]=1[C:6]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([N+:39]([O-:41])=[O:40])=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Ethoxy-N-(4-nitro-3-trifluromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:19])=[C:8]2[C:13](O)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:22]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:19])=[C:8]2[C:13]([Cl:22])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2ncc(C#N)c(O)c2c1OC
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1OC
Temperature: 110 °C

Procedure:
A mixture of 0.46 g of crude 393F in POCl3 (5 ml) was heated at 110° C. for 1 h. Excess of POCl3 was removed on a rotary evaporator, the residue was dissolved in CH2Cl2, washed with aqueous NaHCO3, dried and concentrated to give 0.37 g of crude 393G which was used in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[N:29]=[C:28]([O:30][CH2:31][C:32]([O:34]CC3C=CC=CC=3)=[O:33])[CH:27]=[CH:26][CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:42])[N:10]1[CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[NH:49][S:50]([CH3:53])(=[O:52])=[O:51].CN(C=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[N:29]=[C:28]([O:30][CH2:31][C:32]([OH:34])=[O:33])[CH:27]=[CH:26][CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:42])[N:10]1[CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[NH:49][S:50]([CH3:53])(=[O:51])=[O:52]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OCC(=O)OCc3ccccc3)n2)C1c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OCC(=O)O)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a mixed liquid of 420 mg of benzyl ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate, 5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon, followed by stirring at room temperature for 15 minutes under a hydrogen atmosphere. After separating the palladium/carbon by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 78 mg of ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=3)[C:16]2=[NH:32])[CH:6]=1)[CH3:2].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:74]1([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[CH2:80][N:81]1[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]1>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:84]4[CH2:85][CH2:86][N:81]([CH2:80][C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[C:87]5[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=5)[CH2:82][CH2:83]4)=[CH:27][CH:26]=3)[C:16]2=[NH:32])[CH:6]=1)[CH3:2]
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(Br)cc3)c3ccccc32)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(N4CCN(Cc5ccccc5-c5ccccc5)CC4)cc3)c3ccccc32)c1
Temperature: 120 °C
Yield: 6.2 %

Procedure:
To a mixture of 3-{3-[3-(4-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester (0.50 g, 0.99 mmol), sodium tert-butoxide (0.26 g, 2.67 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (33 mg, 0.07 mmol) and Pd(OAc)2 (22 mg, 0.10 mmol) at rt was added a degassed solution of 1-biphenyl-2-ylmethyl-piperazine (0.25 g, 0.99 mmol) in toluene (15 ml) and tert-butanol (3 ml). The reaction was heated to 120° C. where it was maintained fro 3 d. After this time, the reaction was cooled to rt and concentrated under reduced pressure. The material that remained was partitioned between H2O and EtOAc and the organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with EtOAc/hexane provided 3-(3-{3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester (42 mg, 6%). HPLC-MS 680 [M+1]+, 341.