Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH3:2].[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:19][CH2:20][C:21]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C:4]1[C:13]([CH2:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:3]=1[CH2:1][CH3:2])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: C=CCOC(=O)CNc1c(CC)cccc1CC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
24.7 Grams of allyl 2,6-diethylanilinoacetate and 11.3 g of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C., and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, allyl N-chloroacetyl-2,6-diethylanilinoacetate. nD21.5 : 1.5288.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]=1.[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]12[CH2:8][CH2:7][CH:6]([CH:5]=[CH:4]1)[CH:11]1[CH:10]2[C:9](=[O:15])[NH:13][C:12]1=[O:14]
Reactant: COC1=CCC=CC1
Reactant: O=C1C=CC(=O)N1
Solvent: ClC(Cl)Cl
Product: COC12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
11 g (0.1 mol) of 1-methoxycyclohexa-1,4-diene are heated under reflux with 0.1 g of tris(triphenylphosphine)-ruthenium dichloride and 8.8 g (0.09 mol) of maleimide in 100 ml of absolute chloroform overnight. The mixture is concentrated and the residue is recrystallized from 100 ml of toluene.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[N:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2C)[C:54]([CH:57]([NH2:65])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N:55][N:56]=1>CN(C=O)C>[CH3:51][C:52]1[N:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:54]([CH:57]([NH:65][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N:55][N:56]=1
Reactant: Cc1ccccc1-n1c(C)nnc1C(N)Cc1ccccc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(C(Cc2ccccc2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 10F (29.2 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.16-8.86 (m, 1H), 7.39 (dd, J=16.8, 8.4 Hz, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (t, J=6.3 Hz, 3H), 6.90 (td, J=51.4, 7.6 Hz, 3H), 4.74-4.51 (m, 3H), 3.10 (s, 1H), 2.94 (dd, J=13.5, 8.9 Hz, 1H), 2.44-2.10 (m, 4H), 2.03 (d, J=4.7 Hz, 3H), 1.59 (s, 4H). MS (m/z) 509 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][CH3:13])[CH:4]=2)[CH2:9][CH3:10])=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccc(O)c(OC)c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)c(OC)c1
Yield: 38.5 %

Procedure:
Following general procedure of McMurry reaction as example 1, step B described, 1-(4-hydroxy-3-methoxyphenyl)propan-1-one (207 mg, 1.15 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (318 mg, 1.15 mmol) to give 188 mg desired product (38.5% yield).
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13](=[O:19])[NH:12][C:11]=2[N:10]=1)([CH3:7])[CH2:3][CH2:4][CH:5]=O.Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[O:8][C:9]2[N:10]=[C:11]3[C:16]([CH2:15][CH2:14][C:13](=[O:19])[NH:12]3)=[CH:17][CH:18]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(CCC=O)Oc1ccc2c(n1)NC(=O)CC2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)Oc1ccc2c(n1)NC(=O)CC2
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
To a solution of 4-methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (335 mg, crude) in DCE (6 mL) was added 2,3-dichlorophenyl-piperazine hydrochloride (335 mg, 1.25 mmol) followed by Et3N (0.35 mL, 2.50 mmol). The mixture was stirred for 10 min and then powdered NaBH(OAc)3 (365 mg, 1.72 mmol) was added. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (395 mg, 0.827 mmol, 67% over 2 steps). The foam was dissolved in Et2O and 1 N HCl in Et2O (0.85 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (386 mg). MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[N:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:21]=1[NH2:22])=[O:17])[CH3:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Yield: 74 %

Procedure:
A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water. The precipitate was filtered and dried in vacuo to furnish 12.87 g (74% yield) of pale yellow crystalline solid. The sample was recrystallized from ethanol m.p. 151-2° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:11]([CH2:23][CH3:24])[CH:10]=2)=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:23]([C:11]1[CH:10]=[C:9]([CH2:8][NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH3:24]
Reactant: CCc1cc(C(=O)Nc2ccncc2)ccc1OCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(CNc2ccncc2)ccc1OCC1CCCCC1
Temperature: 50 °C

Procedure:
To a solution of 23-7 (290 mg, 0.86 mmol) in 5 mL of THF was added 1.7 mL (1.7 mmol) of LiAlH4 (1M in THF) and the resulting solution was heated at 50° C. for 2 h, cooled to 0° C. and quenched with 0.07 mL of water, 0.07 mL of 15% NaOH and 0.2 mL of water. The precipitate was filtered, concentrated and purified by column chromatography (94:6:0.6 CHCl3 /IPA/NH4OH) to afford product 23-8.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Reaction time: 8 h
Yield: 90 %

Procedure:
To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), ethyl 2-bromoacetate (1.1 eq.) potassium carbonate (5 equiv.), and 10 mL of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of the solvent gave 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 90% yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](=[O:16])[C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[OH:2]
Reactant: COc1cccc(OC)c1C
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccccc2F)c(O)c1C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2,6-dimethoxytoluene (20.0 g) and o-fluorobenzoyl chloride (19.8 g) are dissolved in 250 ml of dichloroethane and chilled to 5° C. AlCl3 is added portionwise and when the addition is complete the reaction mixture is allowed to warm to room temperature over 30 minutes, then refluxed 30 minutes. It is then poured into 5% HCl and allowed to stand undisturbed 18 hours. Extraction with ether, followed by drying and concentration, gives crystalline material that is washed with hexane to give 2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone, mp 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[O:9][CH3:10].Br[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=[O:21].[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:14]2[CH:15]=[C:16]([F:18])[CH:17]=[CH:12][C:13]=2[CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(S)ccc1Cl
Reactant: O=C(O)Cc1ccc(F)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(Sc2cc(F)ccc2CC(=O)O)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-3-methoxythiophenol (see Example 30) (36.2 g), 2-bromo-4-fluorophenylacetic acid (see the preceding Example) (39.6 g), potassium hydroxide (20 g) and dimethylformamide (250 ml) is heated to 100° C. while stirring until formation of a homogeneous solution. The greatest part of the dimethylformamide is distilled off under normal pressure, removing also the water arising by neutralization. Dimethylformamide (250 ml), anhydrous potassium carbonate (10 g) and copper (6 g) are added to the residue and the mixture is stirred for 14 hours in a bath heated to 170° C. The solvent is evaporated in vacuo, the residue dissolved in water, filtered and the filtrate made acidic by addition of hydrochloric acid. The separated oily acid is extracted with a large volume of warm benzene. The extract is then worked up, yielding 40 g of the crude 2-(4-chloro-3-methoxyphenylthio)-4-fluorophenylacetic acid which is crystallized from aqueous ethanol or cyclohexane. The pure compound melts at 118°-119° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].[C:22](#[N:24])[CH3:23]>C(N(CC)CC)C>[NH2:24][CH:22]1[CH2:11][CH2:12][CH2:13][N:14]([C:11]2[CH:12]=[CH:13][N:14]3[C:9]([C:10]=2[O:18][CH3:19])=[C:8]([CH2:20][CH3:21])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15]3=[O:16])[CH2:23]1
Reactant: CC#N
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(Cl)ccn2c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCCC(N)C3)ccn2c1=O
Temperature: 40 °C
Reaction time: 120 h

Procedure:
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor A) (0.05 g) is dissolved in acetonitrile (3 ml) and triethylamine (0.3 ml). To this solution is added 3-S-aminopiperidine dihydrochloride (Precursor E) (0.055 g) and the mixture is stirred at 40° C. for five days. The reaction mixture is evaporated and the desired product obtained by recrystallization in isopropyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.[F:32][C:33]([F:38])([F:37])[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:36][CH2:35][CH2:34][C:33]([F:38])([F:37])[F:32])=[O:22])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[S:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Reactant: NCCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)NCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a 30 mL vial containing (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (41 mg, 0.10 mmol) was added DMF (3 mL), followed by 3,3,3-trifluoropropan-1-amine (13.94 mg, 0.12 mmol), HATU (54.1 mg, 0.14 mmol), and DIEA (0.050 mL, 0.28 mmol). The mixture was stirred at room temperature for 30 min after which the reaction was quenched with sat. aq. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo onto silica gel. The crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (38 mg, 0.07 mmol, 72% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.64 (d, J=9.09 Hz, 2H), 7.45-7.56 (m, 3H), 7.42 (d, J=2.02 Hz, 1H), 7.25 (d, J=8.59 Hz, 1H), 6.90-7.02 (m, 5H), 6.47 (d, J=15.66 Hz, 1H), 3.88 (s, 3H), 3.74-3.85 (m, 3H), 3.54 (t, J=7.07 Hz, 2H), 2.34-2.56 (m, 2H). LC/MS (m/z, MH+): 528.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11]Cl)(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH2:13]=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CC#N>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:14]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
To a stirred suspension of dried Chloramine-T (5.10 g, 20.76 mmol) in CH3CN (100 mL) under a nitrogen atmosphere was added methylenecyclohexane (9.98 g, 104 mmol). Phenyltrimethylammonium tribromide (7.80 g, 20.76 mmol) was added in three portions over 10 min. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed on silica gel with an ISCO Combiflash using EtOAc/hexanes (5-30% gradient) to afford the title compound as a white solid (2.66 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]=[N:17][OH:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(-c2ccc(C=O)o2)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(-c2ccc(C=NO)o2)cc1
Reaction time: 1 h

Procedure:
A 250 ml Erlenmeyer flask was charged with 5-(4-methoxyphenyl)-2-furaldehyde (40 g, 0.20 mole) and absolute alcohol (125 ml). A solution of hydroxylamine hydrochloride (14 g, 0.20 mole) in water (25 ml) was added to this suspension. This mixture was stirred for 1 hour, cooled, filtered and washed with isopropanol, yielding 28 g (65.2%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.[S:15](Cl)([Cl:17])=[O:16].Cl>>[Cl:17][S:15]([N:2]([CH3:1])[C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:12])[CH3:13])[CH:6]=1)=[O:16]
Reactant: CNC(=O)Oc1cccc(C(C)C)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CC(C)c1cccc(OC(=O)N(C)S(=O)Cl)c1
Reaction time: 1 h

Procedure:
Four grams 3-isopropylphenyl methylcarbamate were mixed with excess thionyl chloride and heated up to 80° C. until HCl evolution ceased. Excess thionyl chloride was removed by distillation and the residue was subjected to high vacuum (0.1 mm) for 1 hour. NMR of the residue in chloroform-d-TMS gave the following absorptions: δ7.5-6.9 (m, 4H, aromatic protons). δ3.25 (s, 3H, NCH3), δ3.2-2.7 (m, 1H, CH), and δ1.3-1.2 (d, 6H, C(CH3 (2).
Reaction SMILES: [CH3:1][C@H:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH2:3][CH3:4].[ClH:24].C(OCC)(=O)C>>[ClH:24].[CH3:1][C@H:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH2:3][CH3:4]
Reactant: CC[C@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of the compound obtained in step 1 (0.70 g) and 4N hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.40 g, 70%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C([O-])(=O)C.[Na+]>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:27](=[O:29])[CH3:28])=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(N)cc1-c1nnn[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccc(N(C(N)=O)c2cccc(C(F)(F)F)c2)c(-c2nnn[nH]2)c1
Temperature: 0 °C

Procedure:
To a solution of 3-trifluoromethylphenyl-4-amino-2-(5-tetrazolyl)phenyl urea (0.22 g, 0.6 mmol) in 17% aqueous sodium acetate (5 mL), cooled on an ice bath, was added acetic anhydride (1 mL). The reaction was stirred at 0° C. for another hour. The precipitate was filtered off and re-crystallised from 96% ethanol to give 0.12 g of the desired material. M.p. 280-282° C.
Reaction SMILES: [O-][CH2:2]C.[Na+].[C:5]([C:10]1[O:11][C:12]([CH3:17])=[C:13]([OH:16])[C:14]=1[OH:15])([O:7][CH2:8][CH3:9])=[O:6].[I-].[Na+]>C(O)C>[C:5]([C:10]1([CH3:2])[C:14](=[O:15])[C:13]([OH:16])=[C:12]([CH3:17])[O:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC[O-]
Reactant: CCOC(=O)c1oc(C)c(O)c1O
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C)OC(C)=C(O)C1=O

Procedure:
In a 250 ml three-necked flask fitted with a mechanical stirrer and a gas inlet tube is placed a solution of 3.4 g of sodium ethoxide in 100 ml of ethanol. To the stirred solution is added at room temperature, under nitrogen, 9.3 g of 2-carbethoxy-5-methyl-3,4-dihydroxy-furan and 0.5 g of sodium iodide. Gaseous methyl bromide is bubbled through the vigorously stirred reaction mixture at 50°-60° C. till the pH of the reaction mixture reaches 6.5-7.0. The solvent is removed under vacuum and the residue is dissolved in ether. The sodium bromide is filtered off, the ether solution is concentrated under vacuum and the residue is distilled through a short Vigreux column; 2-carbethoxy-2,5-dimethyl-3-oxo-4-hydroxy-2H-furan is collected at 102°-105° C./0.2 mm. Yield 8.1 g (81%), recrystallized from cyclohexane, m.p. 89.8°-90.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:10](C(OC(C)(C)C)=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1c(Cc2ccc(Br)cc2)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1ccc(Cc2cc3ccccc3[nH]2)cc1
Temperature: 0 °C
Yield: 49.5 %

Procedure:
A mixture of t-butyl 2-(p-bromophenylmethyl)indole-1-carboxylate (7) (6.0 g) (prepared, e.g., as described in Preparation 2), 10% sodium hydroxide in water (20 ml), and ethanol (150 ml), was heated under reflux for 6 hours. The mixture was then poured onto a mixture of ice water/dilute brine and extracted twice with ethyl acetate. The extract was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to produce an oil, which then crystallized. The material was recrystallized from methyl t-butyl ether to give 2-(p-bromophenylmethyl)indole (2.2 g), a compound of Formula (8), m.p. 136° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([CH3:14])[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:16].[CH3:17][N:18]=[C:19]=[S:20]>O>[CH3:17][NH:18][C:19]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([CH3:14])[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:16])=[S:20]
Reactant: Cc1cc(C)c2ccc(=O)n(CCN)c2n1
Reactant: CN=C=S
Solvent: O
Product: CNC(=S)NCCn1c(=O)ccc2c(C)cc(C)nc21

Procedure:
A mixture of the free base of 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (700 mg., 0.0032 mole) as prepared in Example 12 and methyl isothiocyanate (180 mg., 0.004 mole) in 5 ml. of water is heated at reflux for 30 minutes. On cooling the reaction, the product is collected by filtration. After recrystallization from methanol, 1-{2-[(N-methylthiocarbamoyl)amino]ethyl}-5,7-dimethyl-1,8-naphthyridin-2(1H)-one m.p. 216.5°-218° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C>[CH:13]1([NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 1 g (5.48 mmol) 4-chloro-3-nitrobenzonitrile, Compound 126, and 1.14 g (11.51 mmol) of cyclohexylamine were heated overnight in 5 mL anhydrous DMF. After cooling to room temperature, the solution was added dropwise into 100 mL H2O stirring vigorously. The solids were collected by filtration and dried under vacuum yielding 1.34 g (100%) bright yellow solids which were used as such without analysis in the next step.