Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[O:12])[C:9](=[CH:13][C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O>C(O)(=O)C>[C:1]1([C:7]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[CH:13]=[C:9]([C:10]([OH:11])=[O:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC(c2ccccc2)=CC1=Cc1ccsc1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccccc2)c2sccc2c1
Temperature: 40 °C
Yield: 64.9 %

Procedure:
5-Phenyl-3-(3-thienylmethylene)-2-furanone (44.7 g), methanesulfonic acid (220 cc) and glacial acetic acid (220 cc) are heated for 1 hour at 120° C. The mixture is cooled to 40° C., poured onto crushed ice and extracted with methylene chloride. The organic phase is washed with water and extracted with normal sodium hydroxide solution. The basic aqueous phase is washed with methylene chloride, acidified to pH 1 by adding an aqueous hydrochloric acid solution, and extracted with methylene chloride. The precipitate formed is filtered off and the organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The evaporation residue and the precipitate are combined and stirred in ethyl acetate in the presence of silica gel (100 g). The silica is removed by filtration and the ethyl acetate evaporated under reduced pressure. This operation is repeated to produce 7-phenylbenzo[b]thiophene-5-carboxylic acid (29 g), m.p. 234° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH:2]([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC1CNc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CC1CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
1,2,3,4-Tetrahydro-3-methylquinoline (51 mg, 0.35 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (15 mL, 0.35 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 8.2 mg (12%) of 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.39 (dd, J=8.25, 2.2, 1H), 7.27 (d, J=2.3, 1H), 7.01 (d, J=8.3, 1H), 4.19 (s, 1H), 3.33 (m, 1H), 2.94 (dd, J=10.1, 10.1, 1H), 2.86 (ddd, J=13.8, 4.7, 1.7, 1H), 2.46 (dd, J=16.6, 10.0, 1H), 2.05 (m, 1H), 1.06 (d, J=6.7, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:32]4[N:37]=[C:36]([NH2:38])[N:35]=[C:34]([NH2:39])[CH:33]=4)=[CH:16][CH:15]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(Cl)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 31.3 %

Procedure:
4-{5-[(3-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180° C. for 40 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (62.0 mg). Yield 31.3%.
Reaction SMILES: [CH:1](Cl)([O:6][CH:7]([F:9])[F:8])[C:2]([F:5])([F:4])[F:3].[F-:11].[Na+]>>[CH:7]([O:6][CH:1]([C:2]([F:5])([F:4])[F:3])[F:11])([F:9])[F:8]
Reactant: FC(F)OC(Cl)C(F)(F)F
Reactant: [F-]
Agent: [Na+]
Product: FC(F)OC(F)C(F)(F)F
Temperature: 283 °C
Reaction time: 24 h
Yield: 21.8 %

Procedure:
A 1 liter autoclave (316SS, Parr) was charged with 399 g (2.2 moles) isoflurane and 84 g (2.0 moles) of sodium fluoride. The reaction mass was heated to 283° C. without stirring. After 24 hours at 283° C., the pressure was 1160 psi. The autoclave was then cooled to ca. 10° C. and the crude products (228 g) transferred by pouring into a distillation flask. Distillation through a four foot vacuum jacketed column packed with glass beads gave 73.4 g CHF2OCHFCF3. The material remaining in the distillation flask was found by GC analysis to be 99.6% isoflurane. Based on the materials isolated the percent conversion was 20% (31% yield). Details of the distillation are given below.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[O:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc2cc[nH]c2cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCCC1
Yield: 53.3 %

Procedure:
Using an analogous procedure to that described in Example 243, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (213 mg, 0.662 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.993 mmol) to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (154 mg, 53%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O1CCCC1.O>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:47]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)(=[O:49])=[O:48])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (664 mg) was added, morpholine-4-sulfonyl chloride (250 mg) was added and the mixture was further stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a colorless oil (yield 370 mg, 78%).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)C>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Yield: 28.7 %

Procedure:
7-Fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naph-thyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 9 g of 4-(4-fluorophenyl)piperazine in 30 cm3 of pyridine for 28 hours. After concentrating the reaction mixture to dryness under reduced pressure (20 kPa) at approximately 60° C., the residue was taken up twice in 30 cm3 of ethanol and concentrated under reduced pressure under the above conditions. The solid was taken up into 50 cm3 of water and 10 cm3 of 30% aqueous potassium hydroxide solution. 20 cm3 of water and approximately 10 cm3 of 10% acetic acid were added to the precipitate formed. The suspension was extracted 3 times with 50 cm3 of trichloromethane. The trichloromethane was concentrated under reduced pressure (20 kPa) and the solid obtained was taken up in 2 times 20 cm3 of ethanol. After crystallizing once from 42 cm3 and then recrystallizing once from 15 cm3 of dimethylformamide, 1.33 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naph-thyridine-3-carboxylic acid were obtained in the form of a brown solid melting at about 304-305° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1-c1ccccc1
Solvent: ClCCl
Product: COc1cc(CCl)ccc1-c1ccccc1
Temperature: 0 °C

Procedure:
(2-Methoxy-biphenyl-4-yl)-methanol (170 mg, 0.79 mmol) [PCT Int. Appl. 1999, WO 9955726 A1 19991104] is dissolved in CH2Cl2 (2 mL) and cooled to 0° C. SOCl2 (1 mL) is then added dropwise. The mixture is then allowed to stir till no starting material left. The volatiles were then removed and the crude product is employed in the next step directly.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.C(=O)(O)[O-:27].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH2:2][CH2:3][OH:27])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: C=CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCCO)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 22 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 24, 765 mg, 2.07 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was treated with a 1.0M borane solution in tetrahydrofuran (4.14 mL, 4.14 mmol). The reaction was allowed to warm from 0° C. to 25° C. over 1 h. At this time, the reaction was re-cooled to 0° C. and treated with ethanol (15 mL) followed by a mixture of a saturated aqueous sodium bicarbonate solution (45 mL) and hydrogen peroxide (15 mL). The resulting mixture was allowed to warm from 0° C. to 25° C. over 1 h. The reaction was then slowly quenched with a saturated aqueous sodium sulfite solution and then extracted with ethyl acetate (3×30 mL). The organics were washed with a saturated aqueous solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-(3-hydroxy-propyl)-urea (173 mg, 22%) as a white foam: [α]23589=37.3° (e=0.075, chloroform); EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1154.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[Si:8]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH2:30])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CN1C(=O)CCC1>[CH2:2]([C:1]1[N:19]([CH2:18][CH2:17][CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:20]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1c(N)cnc2ccccc12
Reactant: CCCCC(=O)Cl
Solvent: CN1CCCC1=O
Product: CCCCc1nc2cnc3ccccc3c2n1CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pentanoyl chloride (3.7 mL) was added dropwise to a stirred solution of the product from step (iii) (10 g) and TEA (5 mL) in NMP (110 mL) at rt under nitrogen. The mixture was stirred at rt for 2 h then heated to 100° C. for 6 h. After cooling, the reaction mixture was partitioned between diethyl ether/water, the organics were separated, washed with water, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 50-70% EtOAc/isohexane, yield 6.58 g.
Reaction SMILES: [Li]CCCC.[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].Br[CH2:22][CH2:23][CH2:24][Cl:25].[NH4+].[Cl-]>O.C1COCC1>[Cl:25][CH2:24][CH2:23][CH2:22][C:8]1([C:6]#[N:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
Charge 1780 g of THF and 86.6 g of diisopropylanmine to R1. Cool the mixture in R1 to −40° C.˜−60° C. Add drop-wise 210.5 g of n-BuLi (1.6 eq) into R1 and stir the mixture for 0.5-1 hour. Charge 890 g of THF then 100.0 g of tert-butyl 4-cyanopiperidine-1-carboxylate into R2. Add the solution of tert-butyl 4-cyanopiperidine-1-carboxylate in R2 drop-wise to R1, controling the temperature at −40° C.˜−60° C. Stir the mixture in R1 for 1˜2 hour. Charge 890 g of THF and 130.5 g of 1-bromo-3-chloro-propane into R2. Add the solution of 1-bromo-3-chloro-propane in R2 drop-wise to R1, control the temperature at −40˜−60° C. Stir the mixture in R1 for 3 hours at −40˜−60° C. then slowly warm the mixture to 20˜25° C. and stir for 13˜16 hours. Cool the mixture to 0˜5° C. Add drop-wise 525 g of NH4Cl (saturated aqueous solution) then 500 g of water into R1. Concentrate the mixture to total weight 1000˜1100 g below 40° C. then add 380 g of MTBE. Stir the mixture at 10˜20° C. for 20-40 minutes then allow to stand for 30˜60 mins Separate the aqueous layer and wash the organic layer with 2×500 g of H2O. Concentrate the mixture to 300 g total weight below 50° C. Add 136 g of n-heptane then concentrate the mixture to 300 g total weight below 50° C. Cool the mixture 0-5° C., then add drop-wise 340 g of n-heptane. Stir the mixture in for 5˜10 hours, then filter the suspension. Rinse the flask with 68.0 g of n-heptane, then wash the cake to provide of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate (118 g, 87.2% Assay, 75.4% yield): mass spectrum (m/z): 231 (M+H-tBu). Transfer the cake to a flask and add 610.0 g of Toluene. Concentrate mixture to 500 g total weight below 50° C. The product is stored as a toluene solution until required.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([NH2:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([NH:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:5]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(N)CN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CN(C)C)Nc1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A solution of N1,N1-Dimethyl-propane-1,2-diamine (10 mL, 77.4 mmol) in DMF (40 mL) at room temperature was treated with potassium carbonate (15.26 g, 1.5 equiv.) and 1-fluoro-4-nitrobenzene (8.2 mL, 1 equiv.). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was cooled to room temperature, filtered to remove remaining solid potassium carbonate and diluted with CH2Cl2 (500 mL). The reaction mixture was extracted with H2O (3×500 mL) and dried over anhydrous MgSO4. Following filtration and concentration in vacuo the gelatinous red residue was purified by flash silica gel chromatography (CHCl3 to 1:4 MeOH:CHCl3 gradient eluant) to give N1,N1-Dimethyl-N2-(4-nitro-phenyl)-propane-1,2-diamine as a light brown oil (81.4%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Reactant: C1CCNCC1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(N2CCCCC2)cc1

Procedure:
A suspension of 11.0 g (0.05 mole) of 1,3-dihydro-4-(4-fluorobenzoyl)-5-methyl-2H-imidazol-2-one in 30 ml of piperidine is stirred at reflux temperature for 24 hours. Excess piperidine is evaporated under reduced pressure and the residue is recrystallized twice from a mixture of isopropanol and water to give 11.9 g of the title compound. M.P. 260°-263° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 50 °C
Yield: 98.5 %

Procedure:
To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; J. Med. Chem., 2002, 45, 5769) in dimethylformamide (800 mL) was added 2-iodopropane (93 mL, 926 mmol) and potassium carbonate (190 g, 1.4 mol). The resulting mixture was heated at 50° C. for 16 h, at which time it was allowed to cool to room temperature. The reaction was filtered and the mother liquor diluted with 0.5 N sodium hydroxide (1 L). The resulting mixture was extracted with ether (2×1 L) and the organics washed with 1 N HCl (1 L) and brine (700 mL), dried (MgSO4) and concentrated to give 100 g (˜100%) of methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:19]=1
Reactant: COc1ccc(F)cc1[Mg]Br
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 3-fluoro-6-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(5-fluoro-2-methoxy-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].BrBr.[OH:11]C(O)=O>C(Cl)(Cl)Cl>[OH:11][C:2]([CH3:3])([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:1]
Reactant: CC(C)C(=O)C(C)C
Reactant: O=C(O)O
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)C(C)(C)O

Procedure:
To a stirred solution of 28.3 ml. (0.2 mole) 2,4-dimethyl-3-pentanone in 100 ml. chloroform was added dropwise 10.3 ml. (0.2 mole) bromine in 30 ml. of the same solvent. The resulting mixture was stirred for a few minutes, the solvent evaporated in vacuo, the residue taken up in 100 ml. ethanol. Water, 50 ml., and 10M sodium hydroxide, 50 ml., added. The resulting mixture was stirred at reflux for one hour, diluted with 200 ml. water and extracted with 3×50 ml. ethyl ether. The extracts were dried (MgSO4) evaporated to dryness and the residue distilled to obtain 15.95 g. (61%) of the hydroxy-ketone, b.p. 60°-62° C./18 mm.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]2[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(#N)C>[CH3:25][C:24]([CH3:27])([CH3:26])[CH2:28][C:29]([NH:2][C:3]1[S:4][C:5]2[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[N:7]=1)=[O:30]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)C1CCCc2sc(N)nc21
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCCc2sc(NC(=O)CC(C)(C)C)nc21
Temperature: 0 °C

Procedure:
To a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzthiazole-4-carboxyate hydrobromide (0.92 g, 0.3 mol) in acetonitrile (25 mL) there was added triethylamine (Et3N, 0.41 g, 0.4 mol). Following cooling to 0° C., tert-butylacetyl chloride (0.55 g, 0.4 mol) was slowly added, and the resultant mixture was then stirred overnight at room temperature. Following removal of the solvent and purification by column chromatography, there was obtained ethyl 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate in a yield of 185 mg (corresponding to 19% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.ClCCl.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C=Cc1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
The 21.8 g. of p-chlorocinnamoyl chloride is dissolved in 250 ml. of dichloromethane. To this is added, with stirring, a solution of 35.7 g. of ethyl 4-aminobenzoate in 250 ml. of dichlormethane. The mixture is stirred overnight, then 300 ml. of water are added, stirring is continued for 30 minutes, and the solid is collected by filtration and dried. This solid is boiled in 600 ml. of ethanol and 100 ml. of chloroform, filtered, and the volume reduced to 450 ml., giving a solid, 15.0 g. of which is recrystallized from a mixture of 800 ml. of ethanol and 250 ml. of chloroform by boiling to a volume of 250 ml., giving 13.57 g. of the desired product as off-white crystals, m.p. 203°-204° C.