Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25]I>CN(C)C=O.O>[C:1]([NH:9][C:10]([S:11][CH3:25])=[N:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccccc1N=C(NC(=O)c1ccccc1)SC
Reaction time: 0.5 h

Procedure:
To 0.10 g of 2-[[(benzoylamino)thioxomethyl]amino]-N-methylbenzamide in 2.0 ml of N,N-dimethylformamide was added 0.35 ml of 1N sodium hydroxide at 0° C., followed by 0.04 ml of methyl iodide. The solution was stirred and allowed to reach room temperature over 30 minutes. This was diluted with water to give 0.074 g of N-benzoyl-N'-(2-methylaminocarbonylphenyl)carbamimidothioic acid, methyl ester as colorless crystals, mp 193°-195° C. This compound was reacted with sodium hydride in tetrahydrofuran by refluxing for 21/2 hours to give N-(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl)benzamide, mp 185°-187° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.Cl.[NH2:13][NH:14][C:15]([NH2:17])=[O:16]>O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[N:13][NH:14][C:15]([NH2:17])=[O:16]
Reactant: NNC(N)=O
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: Cl
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1C=NNC(N)=O
Yield: 93.8 %

Procedure:
In 180 ml. of hot water, 9.3 grams (0.06 mole) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde is slurried while 6.7 grams (0.06 mole) of semicarbazide hydrochloride is added portionwise. After 15 minutes of heating, the mixture is cooled in a refrigerator overnight. The solid is then collected and washed with water and methanol, respectively, to give a yellow product, melting point 272°-273° C. (dec.). After drying at 100° for 2 hours under reduced pressure, 11.94 grams of 1-methyl-5-nitro-2-imidazolecarboxaldehyde semicarbazone is formed. This semicarbazone (6.35 grams or 0.03 mole) is added to 10 grams of anhydrous sodium acetate in 50 ml. of glacial acetic acid and 1.25 ml. of bromine is added with continuous stirring. The mixture is heated gradually to give a nearly clear red solution at 50° C. which becomes increasingly turbid with time. After heating at 75 ± 3° for 3 hours, the mixture is cooled and poured on ice. The yellow solid is collected, washed with water, then with methanol, and dried under reduced pressure at 70° C. for 3 hours to give 5 grams of crude 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-oxadiazole, melting point 284°-287° C. (dec.). This material is dissolved in boiling dimethylformamide, ethanol added, and the mixture cooled to give yellow crystals, melting point 291°-293° C. (dec.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:16][C:17]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:26][C:23]4[CH:24]=[N:25][C:20]([O:19][C:18]5[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:17]=5[CH3:16])=[CH:21][CH:22]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1cccc(Oc2ccc(N)cn2)c1C
Solvent: c1ccncc1
Product: Cc1cccc(Oc2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cn2)c1C
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 6-(2,3-dimethylphenoxy)pyridin-3-amine (43 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 402.4. Found 403.1 (M+1)+. Retention time 3.11 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCBr
Reactant: Cc1cccc(S)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCSc1cccc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
The reaction was repeated by cooling a solution of 15.7 grams (0.126 mole) of 3-methylbenzenethiol and 23.3 grams (0.139 mole) of methyl 3-bromopropanoate in about 140 mL of DMF in an ice water bath prior to the addition of 14.1 grams (0.139 mole) of triethylamine. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for an 18 hour period. The reaction mixture was then poured into 200 mL of water, and the mixture was extracted with three 200 mL portions of ethyl acetate. The combined extracts were washed with water, and then with three 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure to a residue, yielding 23.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:9])=[C:4]([NH:25][C:26]([NH2:28])=[O:27])[CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][C:8](=[O:9])[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:4]([NH:25][C:26]([NH2:28])=[O:27])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)COc2ccc(Cl)cc2NC(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Nc1cc(Cl)ccc1OCC(=O)C1CCNCC1
Reaction time: 3 h

Procedure:
A sample of tert-butyl 4-(2-(4-chloro-2-ureidophenoxy)acetyl)piperidine-1-carboxylate (264 mg, 0.64 mmol) was dissolved in CH2Cl2 (8 mL) and TFA (4 mL). The resultant homogeneous solution was stirred for 3 h and concentrated in vacuo. The resultant residue was partitioned between EtOAc and sat. NaHCO3. The phases were separated and the aqueous phase was basified to pH˜14 (paper) with 1N NaOH before being extracted with EtOAc (twice). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford 1-(5-chloro-2-(2-oxo-2-(piperidin-4-yl)ethoxy)phenyl)urea. LC/MS [M+H]+=312.07, [M+Na]+=334.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[C:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]=1[CH3:26]>[Pd].CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]1[CH3:26]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=C(C)CCC2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(=O)CCC2C)c1
Reaction time: 48 h
Yield: 88.4 %

Procedure:
A pressure tube was charged with 66.56B (0.72 g, 2.0 mmol), EtOAc (20 mL), and Pd/C (10 wt. %) (0.22 g, 0.20 mmol). The tube was purged three times with H2 at 45 psi and sealed, and the contents were stirred for 48 hours. The mixture was filtered through silica gel (EtOAc) and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 66.56C (mixture of diastereomers) (0.63 g, 87% yield) as a colorless oil.
Reaction SMILES: C1(C2CCC3C(=CC=C(OC4N=CC(N[S:25]([CH3:28])(=[O:27])=[O:26])=CC=4)C=3)O2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:47][C:48]3[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=3)[CH:43]=2)[O:38]1>>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:47][C:48]3[N:53]=[CH:52][C:51]([NH:54][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:50][CH:49]=3)[CH:43]=2)[O:38]1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1

Procedure:
N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methane sulfonamide in Example 46 starting from 100 mg of 6-[2-(2,4-difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 70). The product was crystallised from a mixture of methanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, 1H), 7.99 (d, 1H, J 2.8 Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.60 (m, 1H), 7.30 (m, 1H), 7.16 (m, 1H), 6.98 (d, 1H, J 8.8 Hz), 6.92-6.86 (m, 3H), 5.31 (dd, 1H, J 10.3, 2.3 Hz), 3.01 (m, 1H), 2.98 (s, 3H), 2.76 (m, 1H), 2.16 (m, 1H), 2.06 (m, 1H).
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:13][CH3:14].[C:24](O)(=O)C>[Zn]>[OH:15][CH:12]([CH2:13][CH3:14])[CH2:11][CH2:10][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:24][C:8](=[O:9])[CH2:2]2
Reactant: CC(=O)O
Reactant: CCC(CCC1CCC2C1C(=O)C2(Cl)Cl)O[Si](C)(C)C(C)(C)C
Agent: [Zn]
Product: CCC(O)CCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 11 substituting the starting material prepared in Example 28, 6,6-dichloro-2-(3-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.2.0]-heptan-7-one{7,7-dichloro-4-[3,[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]bicyclo[3.2.0]heptan-6-one} and isomers (2.4 g, 6.1 mmoles), glacial acetic acid (17 ml), and zinc powder (5 g). The crude produce is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (1.0 g, 4.8 mmoles).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[N:12][C:11]1=2>C(#N)C>[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21]([NH:1][CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:22])[CH:13]=[N:12][C:11]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCN1CCCC1
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCN1CCCC1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
0.500 g. (4.38 mmol) of 1-(2-aminoethyl)-pyrrolidine was heated 100°-110° C. with 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) in a 10 ml round bottom flask with stirring for one hour. Then, 10 ml of acetonitrile was added and the solution was stirred for 15 minutes. The resulting precipitate was collected by vacuum filtration. The solid was washed with acetonitrile and then with ether to yield 275 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(1-pyrrolidinyl)ethyl]propanamide (AIT-0068) as a white solid. Yield: 85%.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.O.[OH-].[Li+]>C1COCC1>[C:10]([O:9][C:7]([NH:6][CH2:5][CH:4]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[C:3]([OH:21])=[O:2])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
The 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid methyl ester (12.3 g, 41.9 mmol) was dissolved in 200 mL 1:1 THF:water and treated with lithium hydroxide monohydrate (2.64 g, 62.9 mmol) at room temperature. The reaction was stirred at room temperature overnight to completion and concentrated in vacuo. The oily mixture was partitioned with water and washed with EtOAc (discarded). The aqueous was treated with solid KHSO4 until pH<2, then extracted with EtOAc. The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo to afford the 3-tert-butoxycarbonylamino-2-p-tolyl-propionic acid as a white solid (10.95 g, 93%). 1H NMR (ca. 1:1 mixture of rotamers) (CDCl3, 400 MHz) δ 10.40-8.40 (br s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.80 or 4.91 (br s, 1H), 3.86 and 3.75 (m, 1H), 3.55 (m, 1H), 3.47 (m, 2H), 2.31 (s, 3H), 1.44 and 1.41 (s, 9H). LCMS (APCI−) m/z 557 [2M−H]−. HPLC R2=2.80 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[CH:42][CH:41]=1)CCC.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[CH:42][CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 5-(tributylstannyl)isothiazole (67.5 mg, 0.180 mmol) and tetrakis(triphenylphosphine)palladium(0) (69.5 mg, 0.060 mmol) in toluene (2.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid. ESI-MS m/z [M+H]+ calc'd for C26H34FN5O5S, 548. found, 548.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1)c1csc(N)n1
Yield: 32.4 %

Procedure:
Ethyl 4-chloro-2-(4-chlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 37.2 g.), thiourea (9.82 g.), sodium acetate 3 hydrate (17.55 g.), water (80 ml.) and ethanol (80 ml.) were treated in similar manner to that of Example P-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 12.86 g.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[C:9]=1[OH:10])[CH:5]=[C:17]([C:16](=[O:21])[CH3:15])[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc(O)c(O)c(C(F)(F)F)c1
Product: CC(=O)C(=Cc1cc(O)c(O)c(C(F)(F)F)c1)C(C)=O

Procedure:
The procedure described in Example 7 was repeated using 2.06 g of 3,4-dihydroxy-5-trifluoromethyl-benzaldehyde and 1.00 g of 2,4-pentanedione. Yield 1.39 g (45%), m.p. 198°-205° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)([O-:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl.[Cl-].[Na+].O>[N+:11]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH:20]=[O:21])[CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccnc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccn1
Temperature: -78 °C

Procedure:
To cooled solution of oxalyl chloride (0.533 g, 4.18 mmol) in DCM (2 mL) at −78° C. under nitrogen was added dimethyl sulfoxide (0.593 mL, 8.37 mmol) dropwise. After 30 minutes (4-nitro-pyridin-2-yl)-methanol (17)(0.129, 0.837 mmol) in DCM (2 mL) was added dropwise maintaining temperature at −78° C. After 2 hours the mixture was warmed to −55° C. Triethylamine (1.74 mL, 12.55 mmol) was then added and the mixture allowed to warm to room temperature over 2 hours. Brine (10 mL) was then added and the mixture extracted with DCM (4×10 mL). The combined organics were then dried over MgSO4 and concentrated in vacuo to an oil. The material was used directly without need for purification assuming quantitative conversion.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=1)=[O:22]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 3-aminobenzamide (310 mg, 2.3 mmol) in 7.6 mL of THF at 0° C. was added triethyl amine (0.63 mL, 4.6 mmol) followed by 2-bromobenzoylchloride (500 mg, 2.3 mmol). The reaction was stirred at 0° C. for 15 minutes and partitioned between water and dichloromethane. The layers were separated, the organics dried and solvent removed to give 2-bromo-N-(3-carbamoylphenyl)benzamide which was used for coupling without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[F:13][C:14]([F:33])([F:32])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][C:25](=[O:27])[NH:24][C:23]([CH3:28])=[C:22]2[C:29](O)=[O:30])=[CH:17][CH:16]=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[C:8]([NH:11][C:29]([C:22]3[CH:21]([C:18]4[CH:19]=[CH:20][C:15]([C:14]([F:33])([F:13])[F:32])=[CH:16][CH:17]=4)[CH2:26][C:25](=[O:27])[NH:24][C:23]=3[CH3:28])=[O:30])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: Nc1cc2c(Cl)n[nH]c2cc1F
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2cc3c(Cl)n[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.8 %

Procedure:
The product from Example 39, Step 2 (125 mg, 0.668 mmol, 1.0 equiv) was combined with the product from Example 5, Step 2 (200 mg, 0.668 mmol, 1.0 equiv), EDC (153 mg, 0.802 mmol, 1.2 equiv) and Et3N (112 μL, 0.802 mmol, 1.2 equiv) in DMF (2 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-75% CH3CN/H2O, 0.1% TFA over 20 minutes, retention time 13.9 min) to provide 15 mg (5%) of the title compound as a white solid. MS (ES+) m/e 467 [M+H]+
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([CH:20]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH:37]4[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:30][CH:29]=3)[CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[CH:37]1([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH:20]([C:17]3[NH:16][C:15]([C:12]4[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:19][CH:18]=3)[CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:39][CH2:38]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(OCc4ccccc4)cn3)[nH]2)cc1)C1CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of 5-(benzyloxy)-2-(5-[1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrrol-2-yl)pyridine (1.97 g) in a mixed solvent of ethanol (30 mL) and tetrahydrofuran (30 mL) was added 10% palladium carbon (200 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20, volume ratio) to give the title compound (1.62 g, yield 99%) as a yellow amorphous solid. MS: 453 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]2[CH2:11][O:12]C(C3C=CC=CC=3)[O:14][C:8]2=[CH:7][CH:6]=1)[OH:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]([CH2:11][OH:12])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4]
Reactant: Clc1cccc(Cl)c1COCCOCCCCCCBr
Reactant: NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCc1nc(C(O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)ccc1O
Temperature: 70 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) (93 mg) and 2-({2-[(6-bromohexyl)oxy]ethoxy}methyl)-1,3-dichlorobenzene (98 mg) in dimethylformamide (1 ml) and diisopropylethylamine (0.2 ml) was heated to 70° C. for 4 h and then at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated to dryness. The residue was dissolved in ethanol and applied to an SCX-2 cartridge (10 g) eluting with ethanol, followed by 10% aqueous ammonia in ethanol. The ammoniacal fractions were concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 ml) and water (2 ml) and the mixture was heated to 70° C. for 40 min. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3). Appropriate fractions were combined and concentrated and the residue dissolved in acetic acid and re-evaporated to dryness to give the title compound (124 mg). LCMS RT=2.46 min, ES+ve m/z 487/489/491 (M+H)+.