Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:16]([CH2:17][C:5]2=1)[CH2:15][CH2:14][CH2:13]3.ClC1C=CC2NC3CCN4C(C=3C=2C=1)CCC4.Br[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.C(N(CC)CC)C>CCO.CCOC(C)=O>[F:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][N:7]2[C:8]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[C:11]3[CH:12]4[N:16]([CH2:17][CH2:5][C:6]2=3)[CH2:15][CH2:14][CH2:13]4)=[CH:39][CH:40]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Clc1ccc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: Clc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccc(CCn2c3c(c4cc(Cl)ccc42)C2CCCN2CC3)cc1

Procedure:
A mixture of 7-chloro-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole and 10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (non-separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and 1-(2-bromoethyl)-4-fluorobenzene (577 mg, 2.84 mmol, 1.4 equiv) were heated at 95° C. with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2×10 mL), and once with brine, then dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC. Column: ZORBAX SB C18, 4.6×250 mm, 5μ, retention time (min): 9.71, purity: 95.20%;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1([CH2:43][CH2:44]CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:44][CH2:43][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCN1CCCCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCN4CCCCC4)cc3C)c2cc1OC
Yield: 118.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-piperidino-1-propanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (90 mg, yield 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.O>O1CCCC1>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([OH:16])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC1CC2CCC(C1)N2Cc1ccccc1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
In tetrahydrofuran (16 ml) was dissolved 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (1.0 g, 4.64 mmol), and a 1M-diisobutylaluminum hydride/toluene solution (11.6 ml, 11.6 mmol) was added dropwise thereto at −78° C. over a period of 10 minutes and stirred for another 1 hour. Water was added dropwise thereto to quench the excess reactants, and the resulting mixture was separated by the addition of a 2N-aqueous hydrochloric acid solution and ethyl acetate. The aqueous layer was adjusted to pH 10 or lower with a 2N-aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-ol (886 mg, 88%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.Cl[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.[C:35](=O)([O-])[O-].[K+].[K+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:35])=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3C)nncc2c1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (63 mg, 212 μmol) (obtained by method C below), 2-chlorophenylboronic acid (40 mg, 254 μmol) and tetrakis(triphenylphosphine)palladium (12 mg, 11 μmol) in DME/ethanol (4:1) (5 mL) was treated with 2 M aq. potassium carbonate (317 μl, 635 μmol). The mixture was warmed to 85° C. and stirred for 3 h. The mixture was cooled to RT and purified by flash chromatography (silica gel) eluting with 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia MeOH/DCM to give N-cyclopropyl-4-methyl-3-(1-o-tolylphthalazin-6-yl)benzamide. MS (ES+): 394 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)[CH:16]=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH3:23][Li].Cl>C1COCC1>[C:1]1([CH:16]([CH:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[CH3:23])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CN(C)C=C1C=CC=C1
Agent: Cl
Solvent: C1CCOC1
Product: CC(c1cccc2c1Cc1ccccc1-2)C1C=CC=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The cyclopentadienyl-type ligand, (fluorenyl)(cyclopentadienyl)(methyl)methane was prepared as follows. A solution of 5.0 g fluorene (0.030 mole) was treated with 0.030 mole n-butylithium in 200 mL THF and stirred for two hours at room temperature. Then 0.030 mole 6-(dimethyl)aminofulvene was added and the mixture was stirred for five hours. The deep red solution was then reacted with 0.060 mole methyllithium and the mixture was refluxed for 8 to 10 hours to form a dianion. The reaction product was hydrolysed very slowly with cooling. The reaction vessel was cooled in a dry ice bath and the reaction mixture was hydrolysed by very slow dropping of a solution of aqueous HCl in THF. The thus produced CHMe-bridged ligand was extracted with pentane, dried over sodium sulfate, and the solvent was evaporated.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1([CH2:17][OH:18])[C:10](CO)=[CH:11][CH:12]=[CH:13][CH:14]=1.C[C:20](C)=[O:21]>CS(O)(=O)=O.O>[CH:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1.[OH:18][CH2:17][C:9]1[CH:14]=[CH:13][C:12]([CH2:20][OH:21])=[CH:11][CH:10]=1
Reactant: CC(C)=O
Reactant: OCc1ccccc1CO
Agent: CS(=O)(=O)O
Agent: Cc1ccc(O)cc1
Solvent: O
Product: OCc1ccc(CO)cc1
Temperature: 95 °C

Procedure:
38.4 g (0.36 mol) of p-cresol and 35.0 g (0.25 mol) of xylene-α,α'-diol were dissolved under heating, then 0.15 g of methanesulfonic acid was added thereto at 90-100° C. and the mixture was stirred and reacted at the same temperature for 2 hours. After cooling, 100 ml of acetone was poured into and dissolved in the reaction solution and then the solution was poured into 2,000 ml of water, stirred and then allowed to stand, after which the supernatant was decanted and the residue was dissolved in 100 ml of acetone, poured into 2,000 ml of water and stirred. The solution was allowed to stand, the supernatant was decanted and the residue was evaporated to dryness under reduced pressure to give 65.0 g of p-cresol/1,4-dihydroxymethylbenzene polycondensate as faintly yellow-tinted powdery crystals. Mw≈6,700; Mw/Mn=3.50 (GPC with polystyrene calibration).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](C(OC(C)(C)C)=O)[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][C:17]([O:44][CH3:45])=[C:18]([O:40][CH2:41][CH2:42][Cl:43])[CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CS(C)=O>[ClH:43].[ClH:43].[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:20]4[C:15](=[CH:16][C:17]([O:44][CH3:45])=[C:18]([O:40][CH2:41][CH2:42][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH:19]=4)[N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:12]=[CH:11][CH:10]=4)[N:22]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: CCCC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3cc(OCCCl)c(OC)cc3n2)c1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CCCC(=O)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3cc(OCCN4CCN(C)CC4)c(OC)cc3n2)c1
Product: Cl
Temperature: 85 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
To a solution of tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.170 g, 0.299 mmol) in DMSO (2 mL) was added 1-methylpiperazine (0.5 mL). The subsequent mixture was heated at 85° C. for 2.5 h upon which it was allowed to cool to RT and poured into ice-water (100 mL). A precipitate formed which was collected via filtration and it was dried under vacuum. The precipitate was purified via preparative TLC (SiO2, CH2Cl2:MeOH:NH4OH 9:1:0.1). The purified compound was taken up in CH2Cl2 (2 mL) and HCl (4M in 1,4 dioxane, 10 mL) and stirred at RT for 4 h. The volatiles were removed in vacuo and the residue was triturated with Et2O, filtered and dried under vacuum to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)-quinazolin-2-yl)phenyl) butyramide di-hydrochloride salt (0.085 g, 0.128 mmol, 43% over two steps). MS 595 (M+1). HPLC retention time 4.337 mins.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24]C)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH:1]([O:4][C:5](=[O:30])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C)cc3)n(C3CCC3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution [4-(3-cyano-1-cyclobutyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (950 mg, 2.35 mmol) in DCM (10 mL) is added BBr3 (556 uL, 5.9 mmol) over a period of 20 min. The reaction mixture is stirred further for 1 h at room temperature and then water (1 mL) is added. The solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (650 mg, 71%).
Reaction SMILES: I[CH:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[C:26]#[CH:27])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>ClCCl.C(O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[C:26]#[C:27][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:9])=[CH:4][CH:5]=3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(OC)cc2)cc1
Reactant: OC(I)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2ccc(NC(=O)C#Cc3ccc(CO)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.a. from iodobenzyl alcohol and propynoic acid-(4′-methoxybiphenyl-4-yl)amide. Yield: 0.21 g (22.9% of theory); C23H19NO3 (M=357.41); calc.: molecular ion peak (M+H)+: 358; found: molecular ion peak (M+H)+: 358; Rf value: 0.35 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([CH3:26])[C:6]([NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH3:22])=[N:19][CH:18]=2)=[C:13]([O:23][CH3:24])[CH:12]=1)=O.C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#[N:60])C>C(OCC)(=O)C.C(=O)([O-])O.[Na+].C(OCC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:5]2([CH3:26])[CH2:4][CH2:3][CH2:2][N:60]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:8]=[C:6]23)=[CH:32][CH:31]=1
Reactant: CC#N
Reactant: COc1cc(C(=O)NNC(=O)C(C)(CCCCl)c2ccc(Cl)cc2)ccc1-c1cnc(C)o1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1cc(-c2nnc3n2CCCC3(C)c2ccc(Cl)cc2)ccc1-c1cnc(C)o1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of N′-[5-chloro-2-(4-chlorophenyl)-2-methylpentanoyl]-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (4.0 g) and carbon tetrachloride (1.57 mL) in acetonitrile (25 mL) was added triphenylphosphine (8.56 g), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). Another lot synthesized similarly was combined and the mixture was dissolved in diethyl ether. The insoluble material was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a mixture of the purified product in DMSO (50 mL) was added sodium azide (1.88 g), and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, water and saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (50 mL)/water (5 mL) was added triphenylphosphine (7.60 g), and the mixture was stirred at 60° C. for 2.5 hr. The solvent in the reaction mixture was evaporated under reduced pressure. Acetic acid (25 mL) was added to the residue, and the mixture was stirred under heating with reflux for 1 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.80 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:16]([CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]([C:36]1[CH:37]=[C:38]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:51][N:50]=[CH:49][N:48]=2)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1F)#[N:35]>CS(C)=O>[C:34]([C:36]1[CH:37]=[C:38]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:51][N:50]=[CH:49][N:48]=2)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12]1[N:16]([CH:17]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[N:15]=[CH:14][CH:13]=1)#[N:35]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate, (Preparation 883, 2.20 g, 0.00574 mol), potassium carbonate (1.60 g, 0.0116 mol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide, (Preparation 68, 2.50 g, 0.00575 mol) were combined in a 50 mL round bottomed flask and the flask was cooled in ice. Dimethylsulphoxide (15 mL) was added and after a few minutes the ice bath was removed and the reaction was stirred at room temperature for 3 hours under nitrogen. The reaction was diluted with water (50 mL) and extracted with tert-butylmethylether (100 mL) and the organic layer was washed with water (30 mL). The organic extracts were dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo to give the title compound as a white foam (4.76 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][CH2:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43](=[O:44])[CH2:42][O:41][CH3:40]
Reactant: COCC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 55B (0.038 mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.011 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.84 (s, 9 H), 1.52 (m, 2 H), 2.56 (m, 1 H), 2.74 (m, 3 H), 3.26 (s, 3 H), 3.49 (s, 3 H), 3.66 (m, 1 H), 3.82 (m, 3 H), 4.03 (m, 1 H), 4.16 (m, 1 H), 4.31 (d, J=9.56 Hz, 1 H), 4.83 (d, J=5.88 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.14 (m, 8 H), 7.31 (m, 1 H), 7.85 (m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccccc2)n1

Procedure:
Into 800 g of blocks of ice, a solution of 36.9 g of cyanuric chloride in 320 ml of acetone was added dropwise with stirring to prepare a dispersion. 18.6 g of aniline was added dropwise at temperature of 5° C. or lower into the dispersion. At the same time of the addition of aniline, 210 mL of 5% sodium carbonate aqueous solution was added dropwise at temperature of 5° C. or lower with keeping the same dropping rate as in the addition of aniline to the dispersion, to precipitate crystal, whereby 2,4-dichloro-6-phenylamino-1,3,5-triazine was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](=[O:21])[CH2:5][C:6]1[CH:10]=[C:9]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=2)[N:8]([CH3:20])[CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[ClH:1].[N:22]1([CH2:2][CH2:3][C:4](=[O:21])[CH2:5][C:6]2[CH:10]=[C:9]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([N:8]4[CH2:9][CH2:10][CH2:6][CH2:7]4)=[CH:14][CH:13]=3)[N:8]([CH3:20])[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: Cn1cc(CC(=O)CCCl)cc1C(=O)c1ccc(Cl)cc1
Product: Cl
Product: Cn1cc(CC(=O)CCN2CCCC2)cc1C(=O)c1ccc(N2CCCC2)cc1
Yield: 9 %

Procedure:
A 10 g (0.03 mole) sample of 4-chloro-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-butanone was added to 18 mL (0.216 mole) of pyrrolidine and the mixture heated under reflux for 4 h. The solvent was evaporated in vacuo and the residue triturated with Et2O. The mixture was filtered and the filtrate treated with ethereal HCl to give the salt. Recrystallization from CH3CN gave 1.18 g (9% yield) of a yellow solid: mp 203-206° C. 1H NMR (Me2SO-d6) d 1.85-2.05 (m, 10H); 2.87-3.05 (m, 4H); 3.1-3.15 (m, 2H); 3.3-3.4 (m, 4H); 3.45-3.55 (broad s, 2H); 3.9 (s, 3H); 6.62 (d, 2H); 6.96 (s,1H); 7.72 (d, 2H); 7.92 (s, 1H). Anal Calcd for C24H31N3O2-HCl-0.4CH3CN: C, 66.73; H, 7.50; N, 10.67. Found: C, 66.34; H, 7.43; N, 10,33.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+].[NH2:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:17][CH:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]([OH:28])=[O:27])(=[O:13])=[O:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.6 mmol (1.71 g) of 2-naphthylsulphonyl chloride in 10 ml of dichloro-methane and a solution of 7.9 mmol (0.32 g) of sodium hydroxide in 10 ml of water are added slowly in succession to 7.6 mmol (1.25 g) of phenylalanine and 7.6 mmol (0.3 g) of sodium hydroxide in 10 ml of water. The reaction mixture is stirred for 1 hour at room temperature. After decanting, the aqueous phase is washed with dichloromethane and rendered acidic to pH=2 with a dilute hydrochloric acid solution. After extraction with dichloromethane, the organic phase is dried over sodium sulphate and concentrated to yield the expected product.