Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[N:33]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:31][C:32]1[N:33]=[C:34]([CH2:38][C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14][N:13]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:18][CH2:17]2)[CH:35]=[CH:36][CH:37]=1
Reactant: BrCc1cccc(Br)n1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cccc(Br)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.855 ml of diisopropylamine in 15 ml of tetrahydrofuran was added 2.26 ml of a hexane solution containing 2.66 M n-butyllithium at 0° C., followed by stirring the reaction mixture at 0° C. for 30 minutes. After cooling down to −78° C., a solution of 1.54 g of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate in 5 ml of tetrahydrofuran was added to the reaction mixture, and the resultant mixture was stirred at −78° C. for 30 minutes. A solution of 1.00 g of 2-bromo-6-(bromomethyl)pyridine in 5 ml of tetrahydrofuran was added to the reaction mixture, followed by stirring the reaction mixture at −78° C. for 2 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, followed by extracting with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−2/1) to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].Cl>O.C(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1)=[O:23]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccc(Cl)cc2Cl)n2oc(=O)nc2n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4.5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 100 ml. of methylene chloride and 10 ml. of triethylamine, cooled while stirring to about 5° C. and treated with 2.5 ml. of 2,4-dichlorobenzoyl chloride in 20 ml. of methylene chloride. After 1 hour at 0° C., the mixture is diluted with 100 ml. of water and adjusted to pH 4 with hydrochloric acid. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed over silica gel using a mixture of chloroform and methanol (99:1) for the elution. Crystallization of the residue from chloroform and diethyl ether yields 2,4-dichloro-N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 163°-164° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[C:5]([OH:16])[N:4]([CH3:17])[N:3]=1.O=[C:19]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[C:5](=[O:16])[N:4]([CH3:17])[N:3]2[C:21]([OH:22])=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[N:1][C:2]=12
Reactant: Cn1nc(N)c(Cc2cccc(Cl)c2Cl)c1O
Reactant: CCOC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: Cn1c(=O)c(Cc2cccc(Cl)c2Cl)c2nc(-c3ccncc3)cc(O)n21
Yield: 40.7 %

Procedure:
A mixture of 3-amino-4-(2,3-dichlorobenzyl)-1-methyl-1H-pyrazol-5-ol (150 mg, 0.551 mmol) and ethyl 3-oxo-3-(pyridin-4-yl)propanoate (128 mg, 0.662 mmol) in acetic acid (10 mL), was stirred under reflux for 6 h. The reaction mixture was cooled, concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM:MeOH=10:1 to provide the titled compound (90 mg, 41%), as a white solid; LC/MS: MS (ES+) m/e 401 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.55 (s, 3H), 3.82 (s, 2H), 6.07 (s, 1H), 7.12 (dd, J=1.2, 7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.50 (dd, J=1.2, 7.8 Hz, 1H), 7.71 (dd, J=1.8, 4.8 Hz, 2H), 7.76 (dd, J=1.8, 4.8 Hz, 1H), 11.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Solvent: CC#N
Product: COc1ccc(CCN(C)CCCOc2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
In a manner similar to Preparation 56 react 3,4-dimethoxy-N-methylbenzeneethanamine with 1-(3-chloropropoxy)-4-nitrobenzene in acetonitrile to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:25][CH2:26][O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30].S([O-])([O-])(=O)=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:29]([Si:28]([CH3:34])([CH3:33])[O:27][CH2:26][CH2:25][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:5]=[CH:6]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc2cc[nH]c2cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 352 mg of 5-methyl-6-nitroindole in 10 mL DMF was added drop wise 2.2 ml of 1M toluene solution of lithium hexamethyldisilazide. The solution was stirred for five minutes and 0.5 ml (1.1 equivalents) bromoethoxy dimethyl-t-butyl silane was added. The mixture was stirred at 0° C. for 30 minutes and then stirred for 4 hours at room temperature. Sulfate buffer (pH2) was added and the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to yield 300 mg of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][CH3:19].C(OCC)C>CN(C)C=O.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:14][C:13](=[O:15])[N:12]([CH2:17][CH2:18][CH3:19])[N:11]=2)=[CH:8][CH:9]=1
Reactant: CCCBr
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCN1N=C(c2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a suspension of 0.22 g (5.5 mmol) of 60% oily sodium hydride in 10 ml of anhydrous dimethylformamide was added dropwise a solution of 1.0 g (4.5 mmol) of 3-(4-chlorophenyl)-4, 5-dihydropyrazol-5-one in dimethylformamide (5 ml) at 0° C. After 30 minutes of stirring at room temperature, 0.83 g (6.7 mmol) of 1-bromopropane was added dropwise and stirring was continued for another 2 hours. To the reaction solution was added 50 ml of diethyl ether and 50 ml of water, and vigorously agitated. The resulting solution was separated, and the aqueous layer was extracted twice with 50 ml of diethyl ether. The organic layer was combined and washed successively with water and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 1.1 g of the object compound as a colorless oil (yield 92%).
Reaction SMILES: ClC1N=C(/C=C(/C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)\O)C=CN=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[S:48]([NH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])(=[O:50])=[O:49]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1
Yield: 73.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 5, Step A using methyl 3-aminobenzoate (16 g, 105.9 mmol) in DCM (150 mL) and 2,5-difluorobenzene-1-sulfonyl chloride (24.7 g, 116.5 mmol) the title compound was obtained (25.6 g, 73.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06-11.13 (br, 1H), 7.42-7.52 (m, 2H), 7.52-7.77 (m, 4H), 7.78-7.80 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: C([Si](C)(C)[C:6]1[N:10]([CH3:11])[C:9]([C:12]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)([OH:35])[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH:17]=[C:16]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[CH:8][N:7]=1)(C)(C)C.O>C1COCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:34][C:30]1[CH:29]=[C:28]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:12]([C:36]4[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=4)([OH:35])[C:9]4[N:10]([CH3:11])[CH:6]=[N:7][CH:8]=4)[CH:14]=3)[N:19]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:18](=[O:27])[CH:17]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
A solution of 6-[[2-(tert-butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (4.24 g crude) in THF (100 mL) was treated with tetrabutylammonium chloride (1 M in THF, 10.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, poured into H2O (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N HCl (100 mL), aqueous NaHCO3 (100 mL), and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a light green foam. Purification by flash column chromatography (silica, EtOAc:pet. ether:NH4OH 1:1:.01) gave 4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (2.3 g, 68%) as a light yellow solid.
Reaction SMILES: [CH:1]1(/[C:4](/[CH:11]=[CH:12]/[C:13]2([OH:31])[C:24]([CH3:29])([C:25]([F:28])([F:27])[F:26])[CH2:23][C:16]3(OC(C)C(C)[O:17]3)[CH:15]=[C:14]2[CH3:30])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.O>CC(C)=O.Cl>[CH:1]1(/[C:4](/[CH:11]=[CH:12]/[C:13]2([OH:31])[C:24]([CH3:29])([C:25]([F:28])([F:27])[F:26])[CH2:23][C:16](=[O:17])[CH:15]=[C:14]2[CH3:30])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)C1CC1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC(=O)CC1(C)C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
Ethyl (2Z,4E)-3-cyclopropyl-5-[8-hydroxy-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-yl]penta-2,4-dienoate (40 mg, 0.09 mmol) was dissolved in acetone (4 ml) under argon in a round-bottom flask, and a few drops of conc. hydrochloric acid were added. The resulting reaction solution was stirred at room temperature for 4 h and then water was added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z,4E)-3-cyclopropyl-5-[1-hydroxy-2,6-dimethyl-4-oxo-6-(trifluoromethyl)cyclohex-2-en-1-yl]penta-2,4-dienoate (15 mg, 45% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.88 (d, 1H), 6.37 (d, 1H), 6.01 (s, 1H), 5.64 (s, 1H), 4.17 (q, 2H), 2.92 (d, 1H), 2.52 (d, 1H), 2.39 (br. s, 1H, OH), 1.98 (s, 3H), 1.59 (m, 1H), 1.30 (t, 3H), 1.28 (s, 3H), 0.88 (m, 2H), 0.59 (m, 2H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].C1S(=O)(=O)CCC1.[O:16]1[CH2:18][C:17]21[CH2:24][O:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH2:19]2>>[N+:7]([C:27]1[CH:26]=[CH:25][C:22]2[O:23][CH2:24][C:17]3([CH2:19][O:20][C:21]=2[CH:28]=1)[CH2:18][O:16]3)([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: c1ccc2c(c1)OCC1(CO2)CO1
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc2c(c1)OCC1(CO2)CO1
Temperature: 35 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.11 mole of nitronium tetrafluoroborate and 60 g. tetramethylene sulfone is stirred at 10° C. and 0.1 mole of 3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-2'-oxirane, prepared as described in Example 57, Step A, added during 30 minutes. The cooling bath then is removed and the mixture stirred an additional 20 minutes at 35° C., poured into ice and water, the product extracted with ether, the ether solution dried over magnesium sulfate and evaporated. The product obtained following crystallization from a mixture of chloroform and petroleum ether is 7-nitro-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-2'-oxirane.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH:8]1([NH:11][C:12]([C:14]2[C:22]3[CH:21]=[C:20]([C:23]4[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[N:24]=4)[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9]1>CN(C=O)C.C(OCC)(=O)C>[Cl:29][C:28]1[C:23]([C:20]2[S:19][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:12](=[O:13])[NH:11][CH:8]4[CH2:9][CH2:10]4)[C:22]=3[CH:21]=2)=[N:24][C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:35][CH2:36][N:37]([C:6]([NH2:5])=[O:7])[CH2:38][CH2:39]2)=[N:26][CH:27]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)N1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
Trimethylsilyl isocyanate (26 mg, 0.22 mmol) is added to a stirred suspension of 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (50 mg, 0.11 mmol) in DMF (1 mL) and stirred for 2 hours. The mixture is diluted with ethyl acetate (1 mL) then filtered to give the title compound as a yellow solid (43 mg). ES+(m/z) 513 (35Cl) and 515 (37Cl) [M+H].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CNC1C[CH2:22][CH2:21][CH2:20][CH:19]1[NH:24][CH3:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:39][CH2:38]OCC1>C(Cl)Cl.[Cu](I)I.CO>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:5]4[CH:4]=[N:3][CH:2]=[CH:38][C:39]=4[CH2:25][N:24]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: C1COCCO1
Reactant: CNC1CCCCC1NC
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CN1CCCC1
Yield: 18.9 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step -3,3-bromo-4-pyrrolidin-1-ylmethyl-pyridine (I-176a: 290 mg, 1.205 mmol) was refluxed with 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 220 mg, 1.004 mmol), copper iodide (19 mg, 0.1004 mmol), N,N′-Dimethyl-cyclohexane-1,2-diamine (42.7 mg, 0.301 mmol), potassium phosphate (640 mg, 3.012 mmol) and 1,4-dioxane (15 mL) at 120° C. for 12 hours to afford the crude product. The reaction was monitored by TLC (5% MeOH in DCM). Purification by column chromatography on silica gel (5% MeOH in chloroform) followed by preparative HPLC afforded 72 mg of the product (18.9% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:24])=[C:4]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:3]([CH3:24])=[C:4]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cccc(F)c3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(F)cccc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.9 %

Procedure:
In THF/methanol (2:1, 60 ml) was dissolved methyl (2-(3-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.21 g, 3.64 mmol). To the resulting solution was added 1N NaOH (20 ml). After stirring at room temperature for 17 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(3-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.10 g, 15%) as a colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.BrBr.[Li].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:28]([O:27][C:25](=[O:26])[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)[CH3:29]
Reactant: Clc1cc(-c2ccccc2Cl)c(Br)cn1
Reactant: CCOC(=O)Cl
Agent: BrBr
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2.00 g (6.60 mmol) 5-bromo-2-chloro-4-(2-chloro-phenyl)-pyridine in 66 ml tetrahydrofuran 4.3 ml of a solution of n-butyllithium in hexanes (1.6 M, 6.9 mmol) were added dropwise at −100° C. under argon. Thin layer chromatography showed complete bromine-lithium exchange after 5 min. After addition of 0.71 ml (7.3 mmol) ethyl chloroformate the reaction mixture was allowed to slowly warm to −78° C. and stirred at that temperature for 1 h. The reaction mixture was allowed to warm to room temperature over night. Quenching with a small amount of water was followed by dilution with tert-butyl methyl ether and washing with water and brine. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 1.66 g (85%) of the title compound as a light yellow solid.
Reaction SMILES: CN[C@@H:3]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4]1.[C:9]([O:13][C:14]([O:16]C(OC(C)(C)C)=O)=O)([CH3:12])([CH3:11])[CH3:10].[CH2:24]([N:26](CC)CC)C>C(Cl)Cl>[C:9]([O:13][C:14](=[O:16])[NH:26][CH2:24][C@H:3]1[CH2:7][CH2:6][C@@H:5]([OH:8])[CH2:4]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN[C@@H]1CC[C@H](O)C1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a mixture of cis-3-(methylamino)cyclopentanol 113 (1.59 mmol) in DCM (20 mL) was added di-tert-butyldicarbonate (0.35 g, 1.59 mmol) followed by triethylamine (0.45 mL, 3.23 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo to give a yellow oil which was purified by chromatography to give 114 (0.18 g, 52%, over 2 steps) as a white foam.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]1([N:12]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13]2)[CH2:11][CH2:10]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([OH:27])[C:13]2[N:12]([CH:9]3[CH2:10][CH2:11]3)[CH:16]=[CH:15][C:14]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccn(C2CC2)c1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccn(C2CC2)c1C(O)c1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
LDA (1.8M, 18.97 mL, 34.2 mmol) was added dropwise to a solution of methyl 1-cyclopropyl-1H-pyrrole-3-carboxylate (Step 240.6) (4.03 g, 24.40 mmol) in THF (80 mL) at −78° C. and the mixture was stirred for 30 min. A solution of 4-chlorobenzaldehyde (3.77 g, 26.8 mmol) in THF (20 mL) was added at −78° C. The mixture was allowed to warm to −50° C. over 2 hrs, quenched with a saturated aqueous solution of ammonium chloride, and taken up in EtOAc/saturated ammonium chloride solution. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 4:1) to afford the title compound (6.1 g, 79% yield) as a yellow solid. TLC (hexane/EtOAc 4:1): Rf=0.21.
Reaction SMILES: ClC1C=C(Cl)C=C(Cl)C=1[O:10][C:11](=O)[CH2:12][C:13](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:14].[NH2:26]/[C:27](/[CH3:34])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(OCC)(=O)C.CCOCC>BrC1C=CC=CC=1>[CH2:32]([O:31][C:29]([C:28]1[C:13]([OH:14])=[CH:12][C:11](=[O:10])[NH:26][C:27]=1[CH3:34])=[O:30])[CH3:33]
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCOC(C)=O
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1c(O)cc(=O)[nH]c1C
Temperature: 155 °C

Procedure:
A mixture of malonic acid bis(2,4,6-trichloro-phenyl)ester (13.3 g, 0.03 mol) and ethyl 3-aminocrotonate (3.87 g, 0.03 mol) in bromobenzene (25 mL) is heated at 155° C. for 30 minutes. The mixture is cooled to room temperature. Ethyl acetate (50 mL) and ether (50 mL) are added. The solid is collected and purified by filtration through a short silica gel column (25% ethyl acetate/ether) to give 4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester. 1H NMR: (CDCl3) 5.85 (s, 1H), 4.38 (q, 2H), 2.68 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:20])[CH2:13][CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]([NH:11][CH3:10])=[O:20])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CNC(=O)CCNCC(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)CCN(CC(C)C)c1nc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 2.82 g, 12.37 mmol), N-methyl-3-(2-methylpropylamino)propanamide (Intermediate 86; 1.78 g; 11.25 mmol), Triethylamine (1.65 mL, 11.81 mmol) and DCM (40 mL) were combined and stirred over the weekend at room temperature. The reaction mixture was washed saturated aqueous sodium bicarbonate solution and gravity filtered through a PTFE cup and solvent evaporated. The residue was dissolved in DCM and passed through a silica column eluting with a gradient of 30-50% Ethyl Acetate/iso-hexane over 10 column volumes then 50% Ethyl Acetate/iso-hexane. Fractions containing product combined and evaporated to give the title compound as a white solid. (3.26 g, 83%)