Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.[CH3:13][NH:14][CH3:15]>C1COCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1)[CH3:15]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: CNC
Solvent: C1CCOC1
Product: CC(=O)c1cc(CN(C)C)ccc1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
In a solution of 2′-hydroxyacetophenone (10 g, 73.53 mmol) in 12 N HCl (160 mL) at room temperature was mixed with paraformaldehyde (2.43 g, 80.88 mmol) and stirred at 40° C. for 8 hours. The reaction was diluted with water, extracted with CH2Cl2 (3×100 mL), and concentrated using a rotary evaporator to provide 13 g of 5′-chloromethyl-2′-hydroxyacetophenone (98%). To a solution of 5′-chloromethyl-2′-hydroxyacetophenone (4 g, 21.74 mmol) in THF (50 mL) at room temperature was added dimethylamine in THF (13 mL, 26 mmol). The reaction mixture was stirred at 60° C. for 6 hours. It was quenched with water and neutralized with potassium carbonate to pH=8. Extract with CH2Cl2 (3×100 mL) followed by concentration using a rotary evaporator provided 3.86 g of 5′-(N,N-dimethylaminomethy)-2′-hydroxyacetophenone (92%). A solution of 5′-(N,N-dimethylaminomethy)-2′-hydroxyacetophenone (1.4 g, 7.25 mmol) and ethyl isonicotinate (1.1 g, 7.25 mmol) in THF (100 mL) at room temperature was mixed with NaH (1.02 g, 25.375 mmol) and was stirred at reflux for 6 hours. The reaction was quenched with water and extracted with CH2Cl2 (3×100 mL). The volume was reduced using a rotary evaporator to minimal and triturated with hexanes. The solid was collected by filtration to afford 1.85 g of the corresponding diketone (86%). A solution of the above diketone (1.85 g, 26.19 mmol) in HOAc (100 mL) was stirred at reflux for 2 hours. All the solvent was removed using a rotary evaporator to afford a solid residue. It was then re-dissolved in CH2Cl2, diluted with water and neutralized with potassium carbonate to pH=8, extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator The solid residue was purified by column (SiO2, hexanes/EtOAc/MeOH=2:2:1) to afford 1.4 g of the intermediate (80%). A solution of the above intermediate (0.7 g, 2.34 mmol) in CH2Cl2 (20 mL) was mixed with HCl in ether (10 mL, 20 mmol) and stirred at room temperature for 30 min. The solid was collected by filtration and washed with CH2Cl2 and MeOH sequentially to obtain 0.48 g of the 6-((dimethylamino)methyl)-2-(pyridin-4-yl)-4H-chromen-4-one hydrochloride (60%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][S:24]4(=[O:30])=[O:29])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ncc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 54.8 %

Procedure:
Using (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 229 and isothiazolidine 1,1-dioxide (61 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (114 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[SH:21]>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: Sc1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) and 2,4-dichlorothiophenol (202.9 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 1 hour, and then concentrated in vacuo. The resulting residue is treated with water and stirred for 1 hour. The precipitate is filtered, washed with water, air dried, and then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 249.0 mg of 7-[(2,4-dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 126-128° C.; 1H NMR (DMSO-d6) δ 7.47 (dd, J=6, 2 Hz, 1H), 7.54 (d, J=6 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.88 (d, J=2 Hz, 1H), 8.43 (d, J=4 Hz, 1H), 9.09 (s, 1H); MS 336.9, 339.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[S:32][CH:33]=[C:34]([C:36](N(OC)C)=[O:37])[N:35]=3)[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:42][Mg]Br.O>O1CCCC1>[C:36]([C:34]1[N:35]=[C:31]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]3[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[S:32][CH:33]=1)(=[O:37])[CH3:42]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1csc(-c2ccc3nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccc(C)cc4)c3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a suspension of tert-butyl {[2-isobutyl-6-(4-{[methoxy(methyl)amino]carbonyl}-1,3-thiazol-2-yl)-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.23 g, 0.4 mmol) in tetrahydrofuran (10 ml) was added dropwise 3.0 M methylmagnesium bromide (0.4 ml, 1.2 mmol) at 0° C. After the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-(4-acetyl-1,3-thiazol-2-yl)-2-isobutyl-4-(4-methylphenyl)-3-quinolinyl]methylcarbamate (0.20 g, yield 95%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.N1CC[CH2:16][CH2:15][CH2:14]1>CC(C)=O>[C:15](=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][C:6]1=[O:12])([CH3:16])[CH3:14]
Reactant: C1CCNCC1
Reactant: COc1cccc2c1CC(=O)N2
Solvent: CC(C)=O
Product: COc1cccc2c1C(=C(C)C)C(=O)N2
Yield: 18.7 %

Procedure:
A mixture of 4-methoxyoxindole (3.0 g, 18.4 mmol) and piperidine (3.5 mL, 36.89 mmol) in acetone (100 mL) is heated at reflux for 18 hours. The mixture is concentrated to dryness and triturated with methanol (20 mL). Filtration removed 800 mg of unreacted 4-methoxyoxindole. The filtrate is preadsorbed on silica gel (5 g), and purified by flash chromtography (120 g SiO2, 25% ethyl acetate:hexane to 50% ethyl acetate:hexane) to provide 700 mg (19%) of 3-isopropylidene-4-methoxy-1,3-dihydro-indol-2-one. MS (ESI+) 204.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[NH:7][CH:8]=1)(=[O:3])[CH3:2].Br>CC(O)=O>[C:1]([C:4]1[N:5]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[NH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cc2nc(C(C)=O)c[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)c1c[nH]c(Cc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
A solution of XXVI (2.2 g, 0.01 mol), AcOH (10 mL) and 48% HBr (40 mL) was heated at reflux. After 24 hours, the solution was concentrated to dryness, neutralized with NaHCO3 to pH 8.5 and the mixture stirred at room temperature. The suspension was concentrated to dryness mixed with CH3OH (100 mL) and silica gel (20 g) and concentrated to dryness. The solid was placed on a silica gel column and the product eluted with 5% CH3OH--CHCl3 to yield 1.7 g (81%) of XXVII; m.p. 229°-31° C. (CH3CN).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)[CH2:23][CH2:22]1>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:29]3[C:28]4[C:32](=[CH:33][CH:34]=[CH:35][C:27]=4[CH:24]4[CH2:23][CH2:22][NH:21][CH2:26][CH2:25]4)[NH:31][C:30]3=[O:36])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(C5CCNCC5)c43)c(C)c2C1=O
Yield: 26 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 5-(2-diethylamino-ethyl)-3-methyl-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (20 mg, 26.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O>[C:18]([Si:15]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH3:17])[CH3:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
Dissolve 2,4-dichloro-phenol (30 g, 184 mmol) and cool to 0° C. Add imidazole (28 g, 405 mmol) followed by t-butyldimethylsilyl chloride (31 g, 202 mmol). Warm reaction mixture to room temperature, and stir for 20 minutes. Pour reaction mixture into water and extract with ether. Separate layers and wash organics with water, 2× brine, dry over sodium sulfate, filter and concentrate to yield 48.4 g (95%) of tert-butyl-(2,4-dichloro-phenoxy)-dimethyl-silane.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:21][CH:22]([F:35])[O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH:33]=O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>>[F:21][CH:22]([F:35])[O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH2:33][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:4]3[C:3]([CH3:2])=[C:11]4[C:7](=[CH:6][CH:5]=3)[C:8](=[O:12])[O:9][CH2:10]4)[CH2:16][CH2:17]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(CC=O)cc1OC(F)F
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c(CCN2CCN(CCc3ccc(C#N)c(OC(F)F)c3)CC2)ccc2c1COC2=O

Procedure:
2-(Difluoromethoxy)-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 456.5 [M+1]+. (0.16 μM)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][O:20][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1
Reaction time: 2 h
Yield: 61.1 %

Procedure:
3.35 g (11.8 mmol) of 4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 55 ml of THF at RT and treated with 0.57 g (13.0 mmol) of sodium hydride (55% in mineral oil). 1.68 ml=2.03 g (14.1 mmol) of benzoyl chloride was added drop by drop and stirring continued for 2 hours. The reaction mixture was then poured into crashed ice and extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 2.80 g (61%) of the title compound as yellow oil. MS: 389.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][N:3]=1.[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:6][N:7]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1ncc(-c2ccon2)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncc(-c2ccon2)cn1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
A mixture of 2-methyl-5-isoxazol-3-yl-pyrimidine (30 gm), N-bromosuccinamide (49.8 gm), and 98% benzoyl peroxide (13.54 gm) in carbon tetrachloride (1200 ml) was heated to 75° C. temperature. The reaction mixture was stirred at 75° C. for 24 h. The reaction mixture was filtered under suction at 25° C. to 35° C. temperature. The solid was washed with carbon tetrachloride (400 ml). The filtrate was washed with saturated aqueous sodium bicarbonate solution (400 ml×2) and evaporated under vacuum to provide a crude material (52 gm) which upon silica gel column chromatography afforded desired compound in 14 gm quantity (40%), dibromo compound in 16.8 gm and starting material 6.5 gm quantities.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: COc1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of 4-methoxy-phenyl-acetylene (10 g, 0.075 mol) and 4-iodo-anisole (17.65 g, 1.0 eq.) in diethylamine (150 mL) was added Pd(PPh3)2Cl2 (2.65 g, 0.05 eq.) and the reaction mixture was stirred for 30 min at 0° C. To the reaction mixture was then added Cul (1.43 g, 0.1 eq.) and the mixture was stirred at 6 h at 0˜25° C. The reaction mixture was then concentrated and partitioned between ethyl acetate/H2O (200/600 mL). The organic layer was separated, dried and purified on SiO2 (1˜5% ethyl acetate/hexane) to yield 1,2-di(4-methoxy-phenyl)-acetylene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:15][C:16](=[O:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1c(Cl)cccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CCc2c(Cl)cccc2-c2ccccc21

Procedure:
In a manner similar to that of W. S. Johnson and H. J. Glenn, J. Am. Chem. Soc., 71, 1092 (1949), the reaction of 3-(3-chloro[1,1'-biphenyl]-2-yl)propanoyl chloride (5.3 grams, 0.019 mole), aluminum chloride (3.33 grams, 0.025 mole) and benzene (125 ml) gave a brown oil. The oil was subjected to column chromatography on silica gel and eluted with 9:1 chloroform:petroleum ether to give 8-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-one as a solid.
Reaction SMILES: [Cl-].[C:2]1([NH+:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=O.C(O)C>O>[C:2]1([N:8]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:18]3[C:19]4[C:24]([CH2:16][C:17]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[NH+](c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: c1ccc(-n2c3c(c4ccccc42)-c2ccccc2C3)cc1
Yield: 42.7 %

Procedure:
In a 0.25 l bulb were placed 10 g (45 mmol) of N,N-diphenylhydrazinium chloride, 6.0 g (45 mmol) of 2-indanone and 50 ml of ethanol. The thus obtained mixture was heated at reflux for 4 hours and it was poured into water; the residual mixture was extracted with CH2Cl2 (150 ml) and the solvent was evaporated. The wanted compound was isolated by passing the obtained mixture through a column of silicagel, eluting with benzene/hexane=1:2. The resulting solution was evaporated and treated with 10 ml of hexane, obtaining the precipitation of crystals. Said crystals were separated, washed with hexane (10 ml) and finally dried, thus yielding 5.4 g of N-phenyl-5,6-dihydroindeno[2,1-b]indole (yield=45%).
Reaction SMILES: [Li+].[BH4-].[I:3][C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:5]=1[C:6]([NH:8][CH2:9][C:10](OCC)=[O:11])=[O:7].CO>C1COCC1>[OH:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:4]=1[I:3]
Reactant: CCOC(=O)CNC(=O)c1cc(OC)c(OC)cc1I
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(I)c(C(=O)NCCO)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
LiBH4 (63 mg, 3 mmol) was added to a stirred solution of ethyl 2-(2-iodo-4,5-dimethoxybenzamido)acetate (379 mg, 1 mmol) in THF (2 mL) at −10° C. The reaction was stirred for 5 min then methanol (0.22 mL) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 30 minutes and quenched by addition of water. The THF was removed under reduced pressure and the aqueous residue was thoroughly extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulphate and evaporated to give the crude product which was purified by re-crystallization from EtOAc and hexane to give N-(2-hydroxyethyl)-2-iodo-4,5-dimethoxybenzamide (280 mg, 80%) LC-MS (ES-API); rt 7.60 min; m/z calculated for C11H14NO4 [M+H]+ 352.0, found 352.0.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16](Cl)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][CH:18]([CH3:20])[CH2:17][C:16]([NH:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:21]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 51.2 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (1.0 g, 5.0 mmol) and isovaleryl chloride (0.68 mL, 5.5 mmol) in pyridine (10 mL) provided 3-methyl-N-[7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-yl]butyramide (0.73 g). Mp 162-163° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.46; H, 8.04; N, 4.93.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:13][S:12][CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N:1]1([CH2:6][CH:8]2[CH2:13][S:12][CH2:11][CH2:10][NH:9]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C1CSCCN1)N1CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: C1CCN(CC2CSCCN2)C1
Yield: 92.1 %

Procedure:
A solution of 1.6 g of 3-(pyrrolidine-1-carbonyl)thiomorpholine in 200 ml of tetrahydrofuran was added dropwise to a mixture of 1.0 g of lithium alminum hydride and 100 ml of tetrahydrofuran under ice-cooling and a stream of nitrogen. Excess lithium alminum hydride was decomposed using 15 g of sodium sulfate decahydrate. Celite filtration using methylene chloride was carried out. The solvent was concentrated under reduced pressure to yield 1.37 g (93%) of 3-(pyrrolidin-1-ylmethyl)thiomorpholine.
Reaction SMILES: [C:1](OC(N1CC(C(O)=O)C1)=O)(C)(C)[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:25][CH2:24][CH:23]1[C:26]([OH:28])=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH2:24][C:23]1([CH2:1][CH3:2])[C:26]([OH:28])=[O:27])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)O
Product: CCC1(C(=O)O)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the procedure described for Reference Example 15 substituting 1-tert-butoxycarbonylazetidine-3-carboxylic acid with 1-tert-butoxycarbonylazetidine-2-carboxylic acid at Step A. 1H NMR (500 MHz, CD3OD): δ 3.98-3.90 (m, 1H), 3.80-3.62 (m, 1H), 2.36-1.82 (m, 4H), 1.42 (s, 9H), 1.02 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[CH3:15][N:16]([CH:18]=[N:19][S:20]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=2)=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH3:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:17][N:16]([CH:18]=[N:19][S:20]([C:23]1[C:24]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][N:5]3[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]3[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:33][CH:34]=2)=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH3:15]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1

Procedure:
2.1 g of 4-chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull. 1976, 24(5), 960), 3.8 g of 4′-bromomethylbiphenyl-2-sulfonic acid dimethylaminomethylenamide (J. Med. Chem. 1995, 38, 2357) and 2.8 g of K2CO3 were stirred at RT for 30 h in 50 ml of DMF. The reaction mixture was poured onto 500 ml of water and extracted 2 times using 250 ml of EA each time. The organic phase was then washed with 100 ml of water and dried over MgSO4, and the solvent was removed in vacuo. Chromatography on silica gel using MTB yielded 1.9 g of a white, crystalline powder, mp 193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]([OH:10])[C:7]([OH:9])=[O:8].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([O:10][CH:6]([C:5]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:7]([OH:9])=[O:8])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(O)C(=O)O)cc(OC)c1OC
Product: COc1cc(C(OC(C)=O)C(=O)O)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxymandelic acid (80.5 g) was treated with acetyl chloride (150 ml) at room temperature for three hours. The clear solution was concentrated to dryness under vacuum, and the oily residue was crystallized from toluene (280 ml) giving pure α-acetoxy-3,4,5-trimethoxyphenylacetic acid (80.9 g), m.p. 135-139° C.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:17]1([CH2:29][C:30]([NH2:32])=[O:31])[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[CH:18]=1>>[C:17]1([C:29]2[C:30](=[O:31])[NH:32][C:3](=[O:16])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH2:22][CH2:21][CH2:20][N:19]3[CH:18]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Cl)ccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(Cl)ccc12

Procedure:
Beginning with 6-chloroindole-3-glyoxylic acid methyl ester and 2-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetamide, the title compound was prepared as a dark red foam essentially as described in Example 1.