Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24](OCC)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[CH2:1]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCN
Product: CCCCCCCC/C=C\CCCCCCCCCCCCNC(=O)C(C)O
Temperature: 130 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A one-liter, 3-neck flask equipped with a stirrer, thermometer, Dean-Stark receiver and condenser was charged with erucyl amine (320 grams; 1.0 mol), and ethyl lactate (130 grams; 1.1 mol) and stirred at 130° C. for 8 hours under a nitrogen atmosphere. The reaction was followed by total amine value and infrared spectrum analyses. The reaction mixture was then stripped at 135° C., 30 mmHg vacuum for 30 minutes to afford 368 g (94% yield) of N-erucyl lactamide. This product had a total amine value of 1.6; a hydroxy value of 139.8 and a melting point of 50° C. The structure of this product was confirmed by infrared analysis showing disappearance of the absorption band at about 5.7 microns for ethyl lactate and the presence of a strong amide absorption band at about 6.15 microns, along with hydroxy absorption band at about 2.0 to 3.1 microns.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]=[CH:18][CH:19]=[O:20])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(/C=C/CO)cc(OC)c1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: COc1cc(C=CC=O)cc(OC)c1OCc1ccccc1

Procedure:
In substantially the same manner as in Reference Example 35, (E)-3-(4-benzyloxy-3,5-dimethoxyphenyl)-2-propen-1-ol was subjected to oxidation reaction with activated manganese dioxide to yield 4-benzyloxy-3,5-dimethoxycinnamaldehyde. The product was recrystallized from ethyl acetate-hexane to give colorless plates, m.p.114-115° C.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[C:23]([Cl:24])=[C:22]([C:25](=O)[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)Cl>O>[Cl:10][C:11]1[C:23]([Cl:24])=[C:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)[CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc(Cc2ccc(O)cc2)c(Cl)c1Cl

Procedure:
To trifluoroacetic acid (50 ml.) under a nitrogen atmosphere was added 2.27 g. (0.06 mole) of NaBH4 pellets over a period of 30 minutes at 5°. A solution of ethyl 2,3-dichloro-4-(4'-hydroxybenzoyl)phenoxyacetate (prepared as described in Example 1) (3 g., 0.0081 mole) in 30 ml. of methylene chloride was added dropwise at 15°-20° over a period of 20 minutes. The reaction mixture was stirred overnight at room temperature while the NaBH4 pellets slowly dissolved. At this time the reaction mixture was poured into water and the resulting solution extracted with methylene chloride. The organic extract was washed with aqueous NaCL and dried over MgSO4. Evaporation of the methylene chloride furnished a residue which was chromatographed on a silica gel column eluting with increasing amounts of methanol (MeOH) in CH2Cl2. There was obtained 2 g. of white solid, m.p. 102°-103°.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[O:4][N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])[CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:37]([C:36]4[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:27]5[CH:28]=[C:29]6[C:24]([CH:23]=[CH:22][NH:21]6)=[CH:25][CH:26]=5)=[O:32])=[CH:40][CH:39]=4)[NH:18][C:11]=3[CH:10]=2)[O:4][N:3]=1
Reactant: Cc1noc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)n1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3cc[nH]c3c2)cc1
Product: Cc1noc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc6cc[nH]c6c5)cc4)[nH]c3c2)n1

Procedure:
Compound 660 was prepared according to the procedure similar to that described in Scheme III from 1-(3-methyl-1,2,4-oxadiazol-5-yl)methoxy-3,4-dinitrobenzene and 4-(6-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C26H20N6O3: 465.16; found: 465.04.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1.Br[CH:17]1[CH2:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:17]1([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]2)[CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCC1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C2CCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a suspension of sodium hydride (60% in mineral, 817 mg, 20.4 mmol) in N,N-dimethylformamide (30 mL) was added a solution of methyl 1H-indazole-3-carboxylate in N,N-dimethylformamide (20 mL) at room temperature. After stirring for 30 min, bromocyclobutane (3.45 g, 25.5 mmol) was added, and the mixture was stirred at 90° C. for 13 h. After cooling to room temperature, the mixture was poured onto saturated aqueous sodium hydrogencarbonate solution (200 mL), and the aqueous layer was extracted with ethyl acetate/toluene (3:1, 200 mL×2). The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:6 then 1:5) to give 2.21 g (56%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](Cl)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:16]([NH:15][C:12]([C:4]34[CH2:10][CH:8]5[CH2:9][C:2]([NH2:1])([CH2:11][C@@H:6]([CH2:7]5)[CH2:5]3)[CH2:3]4)=[O:13])[CH2:17]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: NC12CC3C[C@H](C1)CC(C(=O)NC1CCN(CCc4ccccc4)C1)(C3)C2

Procedure:
1-Aza-5-methyladamantane-3-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-aza-5-methyladamantane-3-carboxamide.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O[Li].O>O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Reaction time: 10 h

Procedure:
A solution of the methyl 4-[[4-(2,2,3,3,4,4,4-heptafluorobut-1-oxy)anilino]-1-piperidinyl]methyl]benzoate (0.59 g, 1.13 mmol) in a 3 to 1 mixture of THF and water (40 mL) was added LiOH.H2O (8 eq, 385 mg). The reaction mixture was heated at reflux with stirring for 10 h. The reaction was allowed to cool, concentrated, diluted with water (3 mL), and acidified to a pH of 6 with an aqueous solution of 2N HCl. The solid was collected by filtration, dried, and recrystallized from water (5 mL) to give 0.32 g of 4-[[4-(2,2,3,3,4,4,4-heptafluorobut-1-oxy)phenylamino]-1-piperidinyl]methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, 2H), 7.38 (d, 2H), 6.668 (d, 2H), 6.50 (d, 2H), 4.60 (t, 2H), 3.50 (s, 2H), 3.30 (br., 1H), 3.10 (m, 1H), 2.75 (m, 2H), 2.05 (m, 2H), 1.85 (m, 2H), 1.30 (m, 2H) ppm.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18](N(C)C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.OC1C=CC(C(O)=O)=CC=1.ClCC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CN(C)Cc1ccccc1
Agent: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCc1ccccc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 76 %

Procedure:
4-(Phenylmethoxy)benzoic acid. In a modification of the literature method [E. L. Elied, R. P. Anderson, Reactions of esters with targeting amines. I. Benzyl esters from methyl esters and benzyldimethylamine, J. Am. Chem. Soc., 1952, 74, 547-549] a mixture of 4-hydroxybenzoic acid (27.6 g, 200 mmol), chloromethylbenzene (57.0 g, 450 mmol), potassium carbonate (50 g) and sodium iodide (25 g) was boiled under reflux in acetonitrile (500 mL) for 16 h. The suspension was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residue was recrystallised from ethanol to give phenylmethyl 4-(phenylmethoxy)benzoate (48.8 g, 76%). Phenylmethyl 4-(phenylmethoxy)benzoate (48.8 g, 150 mmol) was boiled under reflux with aqueous sodium hydroxide (2M; 250 mL) and ethanol (250 mL) for 4 h. The ethanol was evaporated under reduced pressure. Water (1000 mL) was added. The white solid was collected by filtration, warmed to 65° C. with aqueous sulphuric acid (2M; 300 mL) for 1 h and extracted with warm ethyl acetate. The ethyl acetate solution was dried with anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give 4-(phenylmethoxy)benzoic acid (27.15 g, 80%). The filtrate was washed twice with diethyl ether, acidified by addition of sulphuric acid (2M) and extracted with diethyl ether. Evaporation of the diethyl ether gave a further portion of 4-(phenylmethoxy)benzoic acid (6.0 g, 18%). The total yield was 98%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][C@@H:12]([CH2:16][OH:17])[O:11][C@H:10]1[N:18]1[C:30]2[C:29]3[NH:31][C:32]4[CH:33]=[C:34]([F:39])[C:35]([F:38])=[CH:36][C:37]=4[C:28]=3[C:27]3[C:40](=[O:44])[NH:41][C:42](=[O:43])[C:26]=3[C:25]=2[C:24]2[C:19]1=[CH:20][C:21]([F:46])=[C:22]([F:45])[CH:23]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:47](Cl)([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:47]([O:17][CH2:16][C@H:12]1[O:11][C@@H:10]([N:18]2[C:30]3[C:29]4[NH:31][C:32]5[CH:33]=[C:34]([F:39])[C:35]([F:38])=[CH:36][C:37]=5[C:28]=4[C:27]4[C:40](=[O:44])[NH:41][C:42](=[O:43])[C:26]=4[C:25]=3[C:24]3[C:19]2=[CH:20][C:21]([F:46])=[C:22]([F:45])[CH:23]=3)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:14]([OH:15])[CH2:13]1)([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H](O)[C@@H](OCc2ccccc2)[C@H](n2c3cc(F)c(F)cc3c3c4c(c5c6cc(F)c(F)cc6[nH]c5c32)C(=O)NC4=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 12-[4-deoxy-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo-[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.500 g, 0.79 mmol) in 6 mL of dry DMF, at 5° C. under Ar, was added tert-butyldiphenylsilyl chloride (0.205 mL, 0.79 mmol) and imidazole (0.161 g, 2.37 mmol). After stirring this mixture at room temperature for 20 h it was re-cooled at 5° C. and more tert-butyldiphenylsilyl chloride (0.205 mL, 0.79 mmol) and imidazole (0.161 g, 2.37 mmol) were added. The resulting mixture was stirred at room temperature for 2.5 h and then it was diluted with ethyl acetate, washed (1M NaHCO3, brine), dried (MgSO4) and evaporated. Chromatography (SiO2/20-35% ethyl acetate-hexane) of the residue afforded 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (0.474 g, 69%); MS (ESI−) m/e 870 (M−H)−. To a solution of a portion (0.050 g, 0.057 mmol) of this material in 2 mL of dichloromethane was added a suspension of Dess-Martin periodinane (0.048 g, 0.114 mmol) in 3 mL of dichloromethane and the mixture was stirred for 30 min. The mixture was then diluted with ethyl acetate, washed (cold 30% aq. Na2S2O3,1M NaHCO3, H2O, brine), dried (MgSO4) and evaporated. Prep tlc (SiO2/ethyl acetate-hexane, 2:3) of the residue afforded 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-3-oxo-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.035 g, 70%) as a gum which solidified on standing; MS (ESI−) m/e 868 (M−H)−.
Reaction SMILES: N([O-])=O.[Na+].Cl.[F:6][C:7]([F:11])([F:10])[CH2:8]N.[CH2:12]([C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[OH:27])[CH3:13]>O.C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([CH2:12][CH3:13])[C@H:15]([O:27][CH2:8][C:7]([F:11])([F:10])[F:6])[CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: NCC(F)(F)F
Reactant: CC[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a solution of sodium nitrite (1.8 g, 26.2 mmol in water (7.0 mL) dropwise at ambient temperature to a solution of 2,2,2-trifluoroethylamine hydrochloride (2.9 g, 20.9 mmol) in water (1.7 mL) under nitrogen atmosphere in a 25 mL round bottom flask connected via cannula tube with another round bottom flask containing a solution of trans-tert-butyl 4-ethyl-3-hydroxy-piperidine-1-carboxylate (400 mg, 1.74 mmol), tetrakis(acetato)dirhodium(II) (78 mg, 0.17 mmol) and 500 mg of molecular sieves (3 Å) in DCM (17 mL) under nitrogen atmosphere. Stir the mixture at ambient temperature for 2 hours; filter the mixture; and concentrate the filtrate. Purify the compound by chromatography in a silica gel cartridge eluting with DCM to obtain the title compound as a pale brown waxy solid (140 mg, 75% pure by 1HNMR and can be used without further purification). MS (m/z): 256 (M-tBu+1).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[C:24]([F:29])[C:21]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>O>[C:22]([C:21]1[C:20]([F:19])=[CH:27][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)=[CH:25][C:24]=1[F:29])#[N:23]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)c(C#N)c(F)c2)CC1
Temperature: 100 °C
Yield: 70 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 2,4,6-trifluorobenzonitrile (393 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was purified via flash chromatography using 1:1 hexanes/EtOAc as the mobile phase. Isolated 594 mg (1.76 mmol, 70% yield).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[N:11][C:6]=2[CH:5]=[N:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1C(=O)CCC1.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][N:4]=[CH:5][C:6]=2[N:11]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3n2)c(F)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Nc2ccc3c(N4CCOCC4)nncc3n2)c(F)c1
Reaction time: 0.08 h

Procedure:
A solution of 5-chloro-N-(2,4-difluorophenyl)pyrido[3,2-d]pyridazin-2-amine (80 mg, 0.27 mmol) and morpholine (238 mg, 2.73 mmol) in 0.4 mL of NMP was heated in a microwave at 150° C. for 30 min. It was diluted with 1 mL of water and stirred for 5 min. The precipitated solid was filtered, rinsed sequentially with 2×2 mL of water, 2×2 mL of ether and 2 mL of EtOAc, then dried in a vacuum oven at 45° C. for 18 h to give the title compound as a tan solid. MS (ESI, pos.ion) m/z: M+1=344.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.Cl[C:48]([O:50][CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:49]>>[CH3:53][C:52]([CH3:55])([CH3:54])[CH2:51][O:50][C:48]([N:44]1[CH2:45][CH2:46][N:41]([C:38]2[CH:39]=[CH:40][C:35]([C:32]3[CH:31]=[CH:30][C:29]([CH2:28][C:11]4[N:12]([C:14]5[CH:15]=[CH:16][C:17]([N:20]6[CH2:21][C:22](=[O:27])[NH:23][S:24]6(=[O:26])=[O:25])=[CH:18][CH:19]=5)[CH:13]=[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[N:10]=4)=[CH:34][CH:33]=3)=[CH:36][CH:37]=2)[CH2:42][CH2:43]1)=[O:49]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNCC5)cc4)cc3)cc2)S(=O)(=O)N1
Product: CC(C)(C)COC(=O)N1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1

Procedure:
5-{4-[4-(2,4-Dichloro-phenyl)-2-(4′-piperazin-1-yl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (20 mg, 0.03 mmol) was treated as described in general procedure U using neopentyl chloroformate (9 mg, 0.06 mmol) to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazine-1-carboxylic acid 2,2-dimethyl-propyl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([Cl:28])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCc1ccc(SC)c(C=CC(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCc1ccc(SC)c(C=CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 25 ml of methylene chloride is added 2-methylthio-5-n-hexylcinnamic acid (1.4 g, 0.005 mmol) with cooling in an ice bath. To this mixture is added DMF (0.365 g, 0.005 mmol) and then oxalyl chloride (0.9 ml, 0.01 mmol) dropwise. The bath is removed and the reaction mixture stirred at room temperature for 2 hours to afford 2-methylthio-5-n-hexylcinnamic acid chloride.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:15])[CH2:12][S:11](=[O:14])(=[O:13])[CH2:10]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[O:13]=[S:11]1(=[O:14])[CH2:12][C:9]([CH3:15])([NH2:8])[CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CS(=O)(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(N)CS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(tert-butyloxycarbonyl)-1,1-dioxo-3-methyl-3-thietanamine [prepared in analogy to Example P3, step 1 and Example P1, step 5] (1.7 g, 7.2 mmol) in dichloromethane (20 ml) at 0° C. is treated with trifluoroacetic acid (13 ml) and the reaction mixture stirred overnight at ambient temperature. The mixture is concentrated under reduced pressure, the solid residue suspended in diethyl ether, stirred, filtered and dried. The crude solid product (1.4 g, 78%) with a melting point of 208-210° C. is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2].[CH3:12][Mg]Br>C1COCC1>[F:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:12])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)c(C#N)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
3-Cyano-4-fluorobenzaldehyde (2.17 g, 14.7 mmol) was dissolved in THF (50 mL) then cooled to −70° C. To this mixture was added methyl magnesium bromide (5.34 mL, 16.0 mmol). The mixture was stirred for 1 h, then was quenched with brine and extracted with ether. The ethereal layer was separated, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by MPLC chromatography through a 120 g Redi-sep column using 0-50% EtOAc/hexane eluent to yield 2-fluoro-5-(1-hydroxyethyl)benzonitrile: LC-MS: M+1=166.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].FC(F)(F)C([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=1[CH2:29][CH3:30])=O.C(N(CC)CC)C>ClCCl>[CH2:29]([C:20]1[C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][NH:16][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[CH3:30]
Reactant: CCc1c(CCNC(=O)C(F)(F)F)ccc(OC)c1OC
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1c(CCNC(=O)CCCCC(=O)OC)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
A solution of 6-chloro-6-oxohexanoic acid methyl ester (10 g) in dry dichloromethane (100 ml) was added dropwise to a stirred, cooled solution of Intermediate 2 (10.4 g) and triethylamine (5.65 g) in dry dichloromethane (100 ml). The reaction mixture was stirred for 1 h at room temperature, the solvent was removed in vacuo and the residue was purified by FCC using ether as eluent to give the title compound (15 g) as a white solid, m.p. 37°-39°.