Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:33]=[CH:32][C:26]2[O:27][C:28]([F:31])([F:30])[O:29][C:25]=2[CH:24]=1>C1(C)C=CC=CC=1>[F:31][C:28]1([F:30])[O:27][C:26]2[CH:32]=[CH:33][C:23]([N:10]3[CH2:11][CH2:12][C:8]4([CH2:14][CH2:15][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)[C:9]3=[O:13])=[CH:24][C:25]=2[O:29]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc3c(c2)OC(F)(F)O3)CCC12CCC1(CC2)OCCO1
Temperature: 110 °C
Yield: 76.8 %

Procedure:
To a mixture of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (262 mg, 1.24 mmol, obtained in example 133, step 3), potassium carbonate (790 mg, 3.72 mmol) and cuprous iodide (354 mg, 1.86 mmol) was added a solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (588 mg, 2.48 mmol) in 5 ml toluene under argon. The solution was then degassed by bubbling argon through the mixture for 2 mins after which N—N′-dimethylethylenediamine (266 uL, 2.48 mmol) was added. The sealed tube was closed and the mixture was heated to 110° C. overnight. The reaction mixture was then cooled to room temperature and filtered through a short pad of Celite® using ethyl acetate to wash the mixture through. The solution was then concentrated in vacuo to give a residue which was purified by flash column chromatography (3:7 ethyl acetate heptane) to give the title compound as white solid (350 mg, 75%). MS (m/e): 368.0 [MH+].
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:11]=1[C:12]([CH2:14][CH2:15][C:16](O)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccc(OCC(O)CNC(C)(C)C)c(C(=O)CCC(=O)O)c1
Reactant: NN
Solvent: O
Product: CNc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
By subjecting 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-(methylamino)benzoyl]propionic acid to cyclisation with hydrazine hydrate by a method similar to that described in Example 19(ix), the title compound may be prepared.
Reaction SMILES: [N:1]([C:9]([N:12]=[C:13]=[O:14])([CH3:11])[CH3:10])=[N:2][C:3]([N:6]=[C:7]=[O:8])([CH3:5])[CH3:4].[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCC>[N:1]([C:9]([NH:12][C:13]([N:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:22])=[O:14])([CH3:10])[CH3:11])=[N:2][C:3]([NH:6][C:7]([N:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:22])=[O:8])([CH3:5])[CH3:4]
Reactant: NNc1ccccc1
Reactant: CC(C)(N=C=O)N=NC(C)(C)N=C=O
Solvent: CCCCC
Product: CC(C)(N=NC(C)(C)NC(=O)N(N)c1ccccc1)NC(=O)N(N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4.0 grams (0.0204 moles) of 2,2'-azobis (2-isocyanato-propane) (from Example XXXIII) in 20 ml of pentane in a 50 ml erlenmeyer flask was added 4.42 grams (0.0408 moles) of phenylhydrazine and the reaction mixture stirred for 2 hours at room temperature. The solids that formed were filtered off, washed with a small amount of cold acetone and air dried. The tan powder weighed 4.5 grams (54% crude yield). The product melts at 159°-162° C. with decomposition. The infrared spectrum of the product is in agreement with the structure of the proposed compound (urea type carbonyl at 1670 cm-1 and NH bands at 3270 and 3400 cm-1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>>[CH2:9]([N:1]([CH2:9][CH:11]1[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)[CH:11]1[O:13][CH2:12]1
Reactant: Cc1cccc(N)c1
Reactant: ClCC1CO1
Product: Cc1cccc(N(CC2CO2)CC2CO2)c1
Yield: 100 %

Procedure:
1 mole of N,N-bisglycidyl-m-toluidine was prepared from 4.8 moles of m-toluidine and 2 moles of epichlorohydrin. The excess m-toluidine was required to produce the oxirane ring and was filtered off as the hydrochloride after completion of the reaction.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.[I-].[Li+].Cl>N1C(C)=CC(C)=CC=1C>[OH:2][C:3]1[CH:11]=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2ccoc2c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Oc1ccc2ccoc2c1
Yield: 19 %

Procedure:
To a solution of 6-methoxybenzofuran (16.9 g) in collidine (200 ml) was added lithium iodide (30.5 g), and the mixture was refluxed under argon atmosphere for 1 day and cooled. To the mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid (5 times) and then washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give dark brown oil of 6-hydroxybenzofuran (2.9 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Yield: 82 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.24 g, 4.4 mmol) and 3-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.43 g, 82%) as a light beige solid, mp 226°-228° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:13](=[O:15])[CH3:14])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2,6-Dichloro-3-nitropyridin-4-amine (208 mg, 1 mmol) was added to acetic anhydride (2 mL), and the reaction mixture was refluxed overnight. After cooled to room temperature, the reaction mixture was basified with aqueous Na2CO3 until the pH was 8. The resulting mixture was then extracted with CH2Cl2. The organic layer was separated, dried over Na2SO4, and concentrated to afford the title compound (240 mg), which was used for the next step without further purification. MS (m/z): 250 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([CH3:31])[CH:33]=2)[CH:25]=1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3-methylbenzoic acid were coupled to give the title compound as a white foam (82 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CC=C(c2coc3c(O[C@H](C)c4c(Cl)ccc(F)c4Cl)c(N)ncc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydro-pyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), ethyl isocyanate (0.00310 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD): δ=1.13 (t, J=7.2 Hz, 3H), 1.87 (d, J=6.8 Hz, 3H), 2.48 (br. s., 2H), 3.22 (q, J=7.1 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H), 4.06 (d, J=2.5 Hz, 2H), 6.25 (br. s., 1H), 6.43-6.56 (m, 1H), 7.21 (t, J=8.7 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.65 (s, 1H), 8.16 (s, 1H). MS (ES+): m/z 493.02/495.04 (100/68) [MH+]. HPLC: tR=2.95 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]1[N:24]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:23]2[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=2[N:21]=1.[CH3:37][O:38][CH2:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.ClCCl>>[CH:25]1([N:24]2[C:23]3[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=3[N:21]=[C:20]2[NH:19][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([CH2:39][O:38][CH3:37])[CH:45]=4)[CH:3]=3)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:6]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CO)ccc3n2C2CCCCC2)c2cc(Br)ccc21
Reactant: COCc1cccc(B(O)O)c1
Solvent: ClCCl
Product: COCc1cccc(-c2ccc3c(c2)c(Nc2nc4cc(CO)ccc4n2C2CCCCC2)nn3COCC[Si](C)(C)C)c1
Yield: 103.3 %

Procedure:
In a small microwave tube added (2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-cyclohexyl-1H-benzo[d]imidazol-5-yl)methanol (52.4 mg, 0.0000918 mol), 3-(methoxymethyl)phenylboronic acid (25.1 mg, 0.000151 mol) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (16.2 mg, 0.0000198 mol). The tube was flushed with argon and the contents were dissolved in 1,4-dioxane (1.5 mL) and 2 M sodium carbonate (150 uL). The reaction was microwaved for 10 minutes at 120° C. The cooled reaction mixture was filtered through a syringe filter and the filter washed 3× with methanol. The combined eluents were concentrated to yield 58 mg of crude product used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH2:3][O:2][CH3:1])=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: COCc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1COC

Procedure:
2-Methoxymethylaniline (1.0 g, 7.2 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.9 g, 7.2 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 2 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated. Recrystallisation from ethanol-water afforded 3-butyryl-4-(2-methoxymethyl-phenylamino)-8-methoxyquinoline, m.p. 128°-30°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[N+:12]([O-])([OH:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]=1[O:10][CH3:11])[C:5]#[N:6]
Reactant: COc1ccc(C#N)cc1Br
Reactant: O=[N+]([O-])O
Product: COc1c(Br)cc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-bromo-4-methoxybenzonitrile (5.22 g, 24.62 mmol) was added to rapidly stirring fuming nitric acid (10 ml, 201 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate and water, and then the organic layer was washed with water and brine, dried (sodium sulfate), filtered, and concentrated in vacuo to afford the title compound, which was carried on without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)[C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:36]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCCc1ccccn1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(CCc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 56.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.70 g) and 2-(2-chloroethyl)pyridine (0.42 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.31 g) was obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ccncc1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccncc3)s2)c(C(=O)C2CCCC2)c1
Yield: 25.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(pyridin-4-ylsulfanyl)-thiazol-2-yl]-urea (110 mg, 25%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 4-mercaptopyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reaction time: 2 h
Yield: 5.8 %

Procedure:
A solution of alcohol 92 (10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (12.03 g, 53.45 mmol, 1.05 equiv) at 25° C. and stirred for 2 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc/hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled to 0–5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc/hexane (2×25 mL), and dried in vacuo to afford the desired (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (iodo-alcohol 93, 15; 1 g, 88% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07(t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 11H, J=7.8, 8.7 Hz). C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10](=[O:11])[C:9]2([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]2)[N:8](C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)(O)=[O:2].[NH2:33][C:34]1[CH:35]=[C:36]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:38]1([C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]1=[O:47])[CH2:37]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[F:31][C:29]1[CH:30]=[C:25]([C@H:6]2[N:5]([CH2:4][C:1]([NH:33][C:34]3[CH:35]=[C:36]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:38]3([C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]3=[O:47])[CH2:37]4)=[O:2])[C:10](=[O:11])[C:9]3([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]3)[NH:8][CH2:7]2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21

Procedure:
0.114 g (0.25 mmol) tert-butyl (R)-4-carboxymethyl-3-(3,5-difluoro-phenyl)-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate were stirred together with 67.9 mg (0.27 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 63.3 mg (0.33 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 44.6 mg (0.33 mmol) HOBt, 35 μl (0.25 mmol) TEA and 1.5 ml DMF, overnight at RT. The solvent was spun off and the residue was stirred with 15 ml of a methanolic hydrochloric acid (1.25N) for 1 h at 50° C. The reaction mixture was concentrated by rotary evaporation and the residue was purified by PR-HPLC. The product-containing fractions were concentrated by rotary evaporation and the residue was triturated with diisopropylether. After suction filtering the solid was washed with diisopropylether and dried.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])C.Cl.[CH3:35][O:36][C:37](=[O:43])[C@@H:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[CH3:35][O:36][C:37](=[O:43])[C@@H:38]([NH:42][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[O:19])=[CH:15][CH:16]=2)[C:7]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:5])[CH:39]([CH3:41])[CH3:40]
Reactant: CCOC(=O)c1onc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)c1-c1ccccc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1onc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)c1-c1ccccc1)C(C)C
Yield: 88.7 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-4-phenyl-isoxazole-5-carboxylic acid ethyl ester and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 88.7% yield. Mass (ES+): 531 (M++1); 1H NMR (DMSO-d6) δ: 0.79 (m, 6H), 2.02 (m, 1H), 3.65 (s, 3H), 4.29 (m, 1H), 7.11 (t, 1H), 7.43-7.47 (m, 2H), 7.52 (m, 3H), 7.55 (d, 2H), 7.67 (d, 2H), 7.81 (m, 2H), 8.74 (s, 1H), 8.93 (s, 1H), 9.25 (d, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[Cl:22])[CH:14]=2)=[O:12])=[CH:5][CH:4]=1.[CH3:23]N(C=O)C>>[CH3:23][N:10]([CH2:9][C:6]1[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=1)[C:11]([C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[Cl:22])[CH:14]=1)=[O:12]
Reactant: CN(C)C=O
Reactant: O=C(NCc1ccncc1)c1cc2nccc(Cl)c2s1
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1ccncc1)C(=O)c1cc2nccc(Cl)c2s1
Yield: 23 %

Procedure:
NaH (0.244 g, 6.09 mmol) was added to a solution of 7-chloro-thieno[3,2-b]pyridin-2-carboxylic acid (pyridin-4-ylmethyl)-amide (0.616 g, 2.03 mmol, prepared as described in Example 11) in DMF (10 mL). When the effervescence ceased, Mel (0.576 g, 4.06 mmol) was added dropwise. After 3 h the reaction mixture was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a yellow oil (0.15 g, 23%). MS: 318.0/320.0 (MH+); HPLC Rf: 4.24 min; HPLC purity: 93%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:10])[CH2:9][CH2:8]1.Br[CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14].O>C(#N)C>[CH:7]1([NH:10][CH:12]2[CH2:17][CH2:16][O:15][C:13]2=[O:14])[CH2:9][CH2:8]1
Reactant: NC1CC1
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1OCCC1NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
After potassium carbonate (18.24 g, 132.0 mmol) was added to a solution of cyclopropylamine (5.50 ml, 80.0 mmol) and (±)-α-bromo-γ-butyrolactone (3.32 ml, 42.0 mmol) in acetonitrile (80 ml), the mixture was stirred at room temperature for 8 hours. To the reaction mixture, water was added and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as the eluant to give (±)-α-cyclopropylamino-γ-butyrolactone (4.10 g, yield 73%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:11]=[C:12]=[S:13])=[C:6]([F:14])[CH:5]=1)[CH3:2].[CH3:17][NH:18][NH2:19]>C(O)C>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[C:9]([F:10])=[CH:8][C:7]([NH:11][C:12](=[S:13])[N:18]([CH3:17])[NH2:19])=[C:6]([F:14])[CH:5]=1)[CH3:16]
Reactant: CCN(CC)c1cc(F)c(N=C=S)cc1F
Reactant: CNN
Solvent: CCO
Product: CCN(CC)c1cc(F)c(NC(=S)N(C)N)cc1F
Yield: 98.3 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.9 g (0.012 mole) of 4-diethylamino-2,5-difluorophenyl isothiocyanate with 0.55 g (0.012 mole) of methylhydrazine in 75 ml of ethanol yielded 3.4 g of 4-(4-diethylamino-2,5-difluorophenyl)-2-methyl-3-thiosemicarbazide. The nmr spectrum was consistent with the proposed structure.