Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[PH:14]1(=[O:23])[O:21][CH2:20][CH2:19]C(N)[CH2:17][CH2:16][O:15]1.[CH:24]([N:27](C(C)C)CC)(C)C>ClCCl>[CH2:20]([O:21][P:14]([CH2:24][NH:27][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[N+:11]([O-:13])=[O:12])([O:15][CH2:16][CH3:17])=[O:23])[CH3:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: NC1CCO[PH](=O)OCC1
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Product: CCOP(=O)(CNC(=O)c1cccc(Cl)c1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-chloro-2-nitrobenzoic acid (1 mmol) and aminomethylenediethyl phosphonate (1.1 mmol) in dichloromethane (5 mL)was added diisopropylethylamine (5 mmol) followed by pyBOP (1.5 mmol). The reaction was stirred at room temperature for 3 h and concentrated. The mixture was purified by chromatography to yield N-(diethylphosphonomethyl)-2-nitro-3-chlorobenzamide as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5](/[CH:6]=[N:7]\[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[C:4]([Cl:16])[CH:3]=1.[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C@H:6]([NH:7][S@@:8]([C:10]([CH3:12])([CH3:13])[CH3:11])=[O:9])[C:18]([F:20])([F:19])[F:17])=[C:4]([Cl:16])[CH:3]=1
Reactant: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(Br)cc1Cl)C(F)(F)F
Temperature: 35 °C
Reaction time: 18 h

Procedure:
To a stirring solution of (R,Z)—N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide (1370 mg, 4246 μmol) and (trifluoromethyl)trimethylsilane (943 μl, 6369 μmol) in DMF (5 mL) was added 1,3-bis(1-adamantyl)imidazol-2-ylidene (143 mg, 425 μmol). Reaction stirred at 35° C. for 18 h then quenched with sat NH4Cl (10 mL). Reaction partitioned between EtOAc (40 mL) and 5% NaHCO3 (10 mL). Organic dried over MgSO4, concentrated to and oil from toluene, then purified on silica (80 g) eluting with 20>30% EtOAc/Hex. Product isolated as a white solid.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:16][O:15]1.[SH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]([OH:15])([CH2:16][S:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: Sc1nccs1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: OC(CSc1nccs1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane, methanesulphonate salt, (6 g, 0.0164 m) and 2-mercaptothiazole (6 g, 0.05 m) were heated in glacial acetic acid (200 ml) under refluxed for 4 hours. The solvent was then evaporated and the residue was basified with dilute sodium hydroxide solution and extracted with methylene chloride. The extract was washed once with dilute sodium hydroxide solution, dried (MgSO4) and evaporated to give a pale brown glass (5.4 g) which was chromatographed on silica, eluting with ethyl acetate:ether:methanol:diethylamine 25:75:2:2, to give, after one recrystallization from isopropanol, the title compound 2 g, (32%); m.p. 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc2ccccc2c1C=O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1c(OC)ccc2ccccc12)C(=O)OCC

Procedure:
2-Methoxy-1-naphthaldehyde (25 g, 1.34.10−1 mol) in benzene (200 ml) is heated for 20 hours at reflux in the presence of diethyl malonate (25 ml, 1.65.10−1 mol, 1.23 eq.) and piperidine (2 ml, 2.02.10−2 mol, 0.15 eq.) in a Dean-Stark apparatus. After adding a few additional drops of piperidine, the mixture is returned to reflux for 20 hours. The reaction mixture is diluted with toluene (200 ml) and washed with water (125 ml). After separation of the phases, the organic phase is treated with a 1N hydrochloric acid solution (190 ml), then with a saturated NaHCO3 solution (125 ml) and with a saturated NaCl solution (125 ml). After drying over MgSO4 and evaporation under reduced pressure, the oil obtained is recrystallised from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][CH:11]([F:22])[S:12]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])(=[O:14])=[O:13].[H-].[Na+].C(Cl)Cl.CO>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[S:12]([CH:11]([F:22])[F:10])(=[O:14])=[O:13])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1S(=O)(=O)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1 mmol) and 2-(difluoromethylsulfonyl)aniline (1 mmol) in 10 mL of DMF was added sodium hydride (2 mmol) at 0° C. After the reaction mixture was warmed to room temperature and stirred at 50° C. for 1 hour. After work-up and flash chromatography (CH2Cl2/MeOH 9:1), product was obtained. MS (ES+): 353.96 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]1([CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:7]1([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)Nc1cc(-c2ccccc2)[nH]n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Amino-5-phenylpyrazole (160 mg) was dissolved in pyridine (1 ml) to which was subsequently added 3-phenylpropionyl chloride (0.15 ml), and the mixture was stirred at room temperature for 14 hours and then at 50° C. for 30 minutes. The reaction solution was diluted with ethyl acetate (15 ml), washed with water (15 ml), 10% citric acid (15 ml), 1 N aqueous sodium hydroxide solution (15 ml) and saturated brine (15 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled away under a reduced pressure, and the resulting residue was crystallized from ethanol to obtain the title compound (139 mg) as white crystals (melting point: 168 −170° C.).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:19]=[C:18]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[CH:17]=2)=[CH:8][C:7]=1[CH3:40].[Li+].[OH-].O.Cl>C1COCC1.CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]#[C:31][C:18]2[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH3:40])[CH:8]=3)[CH:21]=[C:20]([C:22]#[C:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:19]=2)=[CH:34][CH:35]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)ccc1OCC(=O)O
Temperature: 0 °C
Reaction time: 7.67 h

Procedure:
To a solution of (4-{3-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (63 mg, 0.11 mmol) in THF (1.25 ml) and methanol (0.25 ml) was added a ice-cold solution of LiOH (1 M, 1.25 ml). The reaction mixture was stirred at 0° C. for 460 min., after which water (10 ml) and aqueous HCl (1M, 1.75 ml) were added. The mixture was extracted with ethyl acetate (2×10 ml), and the combined organic phases were dried and evaporated to give the title compound in 29 mg (48%) yield.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9](Br)[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH3:18][N:19](C)C=O.C(N)CN>O>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9]([C:18]#[N:19])[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: CN(C)C1CCc2[nH]c3c(Br)cccc3c2C1
Solvent: O
Solvent: NCCN
Product: CN(C)C1CCc2[nH]c3c(C#N)cccc3c2C1

Procedure:
3-(Dimethylamino)-8-bromo-1,2,3,4-tetrahydrocarbazole (18.8 g.) (Example 211) and 17.5 g. of cuprous cyanide in 150 ml. of dimethylformamide was heated under reflux for four hours. The warm reaction mixture was poured into a solution of 200 ml. of ethylenediamine in 400 ml. of water. This was mixed thoroughly and extracted several times with chloroform. The chloroform layer was separated and washed with a dilute solution of ethylenediamine, water, saturated salt solution, and evaporated to dryness to give, after recrystallization from benzene, 6.9 g. of 3-(dimethylamino)-8-cyano-1,2,3,4-tetrahydrocarbazole, m.p. 177°-179° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15][C:16](=S)[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C(N(CC)CC)C.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[N:15][C:16](=[N:23][OH:24])[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: FC(F)(F)C(=S)N=c1ccccn1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: ON=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 21.5 h
Yield: 63 %

Procedure:
25 ml of ethanol was added to 1.00 g (3.00 mmol) of the N-[1-((6-chloropyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroethanethioamide (1-20) 1 synthesized by the method in Synthetic Example 4, 1.04 g (15.0 mmol) of hydroxylamine hydrochloride and 2.00 ml (1.50 g, 15.0 mmol) of triethylamine were added thereto in sequence, and the resulting mixture was stirred at 50° C. for 21.5 hours. After the reaction was completed, ethyl acetate and 1% hydrochloric acid were added to the reaction solution to perform liquid separation, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The organic layer was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the subject material. Amount obtained 625 mg (yield 63%).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([N:16]([CH3:18])[CH3:17])[C:8]([O:14][CH3:15])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1.[Cl-].[NH4+]>CCOCC>[Br:4][C:5]1[CH:6]=[C:7]([N:16]([CH3:18])[CH3:17])[C:8]([O:14][CH3:15])=[C:9]([C:11]([OH:13])([CH3:1])[CH3:12])[CH:10]=1
Reactant: C[Mg]Br
Reactant: COc1c(C(C)=O)cc(Br)cc1N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1c(N(C)C)cc(Br)cc1C(C)(C)O
Temperature: -70 °C

Procedure:
A solution of methylmagnesium bromide in ether was added to a solution of 1-[5-bromo-3-(dimethylamino)-2-methoxyphenyl]-1-ethanone (4 g) in diethyl ether while stirring at −70° C. After stirring at the same temperature for 30 minutes, saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield the title compound (3.4 g) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1>O>[Cl:32][C:33]1[C:38]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A first stock solution was prepared consisting of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 1.77 g, 4.8 mmol), bis(tri-cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 168 mg, 0.25 mmol), and dioxane (approximately 100 mL). A second stock solution was prepared consisting of potassium carbonate (1.99 g, 14.4 mmol) and water (approximately 10 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing 2-chloropyridine-3-boronic acid (ASDI Incorporated, Newark, Del.; 94 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min and then passed through a silica gel column (1 g of silica), and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added and the solvents were removed in the Genevac. Aqueous methanol (50%; approximately 2 mL) was added, then the vial was centrifuged and the solvent was removed. This process was repeated and then the sample was dried overnight in the oven to give 3-[4-(2-chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid. Mass spectrum MH+=340.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6](C=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C([O-])([O-])=[O:17].[K+].[K+].O>CN(C=O)C>[OH:17][CH2:14][CH:13]1[CH2:11][O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[O:15]1
Reactant: ClCC1CO1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC1COc2ccc(Br)cc2O1
Temperature: 90 °C
Yield: 44 %

Procedure:
To a stirred solution of 5-bromosalicylaldehyde (5.0 g, 24.9 mmol), and epichlorohydrin (5.6 mL, 72.1 mmol) in 20 mL of DMF at 80° C. was added K2CO3 slowly in portions. The resulting mixture was then heated at 90° C. for 3 h. Reaction was then stopped, water was added, extracted with diethyl ether. The organic extracts were washed with water, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified on a SiO2 flash column chromatography eluting with 15-30% EtOAc/hexanes to give 2.82 g (44%) of the title compound as colorless oil.
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1C=CC=CC=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=[O:46])[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O>[P:1]([O:11][CH2:12][CH3:13])([O:3][CH2:4][CH3:5])([O:46][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added N,N-dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrfuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrfuran (35 mL) at 0° C. under argon gas, then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>O1CCOCC1.C(N(CC)CC)C>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:26]([C:25]4[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a stirred solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtained in Example 214) (2.8 g, 11.9mol) in 1.4-dioxane (150 mL) and triethylamine (7 mL) was added a solution of N-acetylsulfanilyl chloride (3.5 g, 15 mmol) in 75 mL of 1,4-dioxane at room temperature. The reaction was stirred for 18 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride and washed with diluted hydrochloric acid. The white solid in water layer was collected and dried to give the title compound as a white solid (2.5 g, 43%); 1H NMR (300 MHz, DMSO-d6) δ 1.92 (brs, 4H), 2.06 (s, 3H), 3.68 (brs, 4H), 3.93 (s, 4H), 7.06 (d, J=8.4 Hz, 2H), 7.33 (brs, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0Hz, 2H), 10.24 (brs, 1H), 10.38 (s, 1H); MS (ES) m/z: 432.3 (MH+); HRMS Calcd. for C21H25N3O5S(M+): 431.1515. Found: 431.1530.
Reaction SMILES: [Br:1]Br.[C:3]([Si:7]([CH3:24])([CH3:23])[N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=[C:11]2[CH:10]=[CH:9]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:8]([Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:24])[CH3:23])[CH:9]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccnc3)cnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccnc3)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of bromine (0.166 mL, 0.0032 mol) in 1 mL of CCl4 was added dropwise to a stirred solution of 20 (1.0 g, 0.0032 mol) and pyridine (0.314 mL, 0.0039 mol) in dry CHCl3 (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then neutralized with 10 mL of a mixture of sodium bicarbonate-sodium thiosulfate (1:1). The organic layer was separated and further extracted with dichloromethane (3×10 mL) and the combined organics dried and concentrated in vacuo. The residue was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 0.97 g (78%) of the desired material 21. 1H NMR CDCl3 8.9 (s, 1H), 8.55 (d, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (dd, 1H), 7.2 (s, 1H), 0.9 (s, 9H), 0.5 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:39])[CH:28](Br)[CH2:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[O:24][C:7]1[CH:6]=[N:5][N:4]([CH:28]([CH2:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])[C:27]([OH:26])=[O:39])[C:3](=[O:15])[CH:2]=1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)Cc1c(F)cccc1F
Reactant: Oc1c(F)cccc1F
Product: O=C(O)C(Cc1c(F)cccc1F)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-(2,6-difluoro-phenyl)-propionic acid methyl ester (Intermediate 15) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid as a light yellow solid (1.35 g, 98% for the final step). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.42 (d, J=7.6 Hz, 2H), 5.47 (t, J=7.6 Hz, 1H), 6.00 (d, J=2.7 Hz, 1H), 6.93-7.09 (m, 2H), 7.22-7.55 (m, 4H), 8.20 (d, J=2.7 Hz, 1H), 13.38 (br s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][CH2:25][C@H:26]([NH2:30])[C:27]([OH:29])=[O:28].C(N(CC)CC)C>C(O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([NH:30][C@@H:26]([CH2:25][CH3:24])[C:27]([OH:29])=[O:28])=[O:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 81.5 %

Procedure:
The title compound is prepared by the procedure of Example 255 using 29.46 g of product from Example 254, 9.5 g of L-2-aminobutyric acid, 25.5 ml of triethylamine and 1112 ml of 4:1 ethyl alcohol/water to give 21.2 g of the desired product after chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH:17]1([NH:22][CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([N:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:23])=[O:16])=[CH:3][N:2]=1
Reactant: O=C(Nc1ccnnc1)Oc1ccccc1
Reactant: CNC1CCCC1
Solvent: C1CCOC1
Product: CN(C(=O)Nc1ccnnc1)C1CCCC1

Procedure:
A stirred solution of 2.0 grams of phenyl N-(4-pyridazinyl)carbamate (prepared as in Example 2, Step A) and 0.9 gram of N-cyclopentyl-N-methyl amine in tetrahydrofuran is heated under reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to a residue. The residue is purified by column chromatography on silica gel to yield N-(4-pyridazinyl)-N'-cyclopentyl-N'-methylurea.
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[O:7]([C:4]1[CH:3]=[CH:2][S:1][CH2:6][CH:5]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=C1C=CSCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1=CCSC=C1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.1 mmol, synthesized as described in Richards et al. J. Org. Chem. 46, 4836-4842 (1981)) was dissolved in CH2Cl2 (130 mL) and triethylamine (5.47 mL, 39.4 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.8 mmol) was then added. After 10 minutes, the volatiles were removed in vacuo at 25° C. The resulting yellow oil was passed through a short column of SiO2 eluting with 3% TEA in hexanes to yield 1.82 g (7.97 mmol, 61%) of compound 1A as an orange oil.