Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[O:26][CH2:25]1>>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:31]5[CH:32]=[CH:33][C:27]6[O:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=6[CH:30]=5)[CH2:3][CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Product: Cl
Product: O=C1COc2ccc(CNC3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)CC3)cc2N1
Yield: 69 %

Procedure:
The free base of the title compound was synthesised from 4-[(4-amino-1-piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2002056882, Example 5(b)), according to the general method of Example 2(h), in 69% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(OCC(C)C)=O.[CH3:38][N:39]1CCOCC1.CN>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH:39][CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at −10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stirred for 18 hours. The reaction mixture was concentrated in vacuo, suspended in water, filtered and washed with water, ethyl acetate and diethyl ether. 1H NMR (400 MHz, CD3OD) δ 8.03 (dddd, J=3.0, 6.4, 9.2 and 11.6 Hz, 1H), 7.81 (dd, J=3.0 and (0.2 Hz, 1H), 7.66 (q, J=10.4 Hz, 1H), 7.47 (t, J=12 Hz, 1H), 7.06 (t, J=12 Hz, 2H), 6.67 (s, 1H), 5.38 (s, 2H), 2.91 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.50 (1F), −115.97 (1F), −120.16 ppm. ES-HRMS m/z 481.0346 (M+H calcd for C21H17BrF3N2O3 requires 481.0369).
Reaction SMILES: C(O[CH:4]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5]1)C.S(=O)(=O)(O)O.C(O)(=O)C.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1CCCCC1.C(OCC)(=O)C>[OH:25][C:19]1[CH:24]=[CH:23][C:22]([CH:4]2[NH:9][C:7](=[O:8])[CH2:6][CH2:5]2)=[CH:21][CH:20]=1
Reactant: CCOC1CCC(=O)N1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(O)cc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.3 %

Procedure:
12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of concentrated sulphuric acid and 90 ml of glacial acetic acid were charged initially at 0° C. and admixed a little at a time with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-Up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once with water and once with saturated aqueous sodium chloride solution, dried and evaporated. After some time, γ-2-hydroxyphenyl-γ-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained on evaporation was stirred with 1:1 mixture of cyclohexane/ethyl acetate and afforded on filtration with suction 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was evaporated. Recrystallization from dichloromethane/hexane gave a further 3.35 g (total 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO.O>[CH:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:23])([CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)NC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 79.7 %

Procedure:
A mixture of methyl 2-(3-(isopropylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (120 mg, 0.315 mmol) in methanol (4.8 mL) and 2N sodium hydroxide aqueous solution (3.2 mL, 6.4 mmol) was heated to reflux for 2 h. Thin layer chromatography (petroleum ether:ethyl acetate=3:1) and LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate/tetrahydrofuran, washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 92 mg of 2-(3-(isopropylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 80%. LC-MS (M+1)=367.2.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2.[N:17]([O-])=[O:18].[Na+].[OH-].[Na+]>CC(O)=O.O>[CH3:1][NH:2][C:3]1[C:4]([N:17]=[O:18])=[C:5]2[N:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=N[O-]
Reactant: CCOC(=O)c1c(NC)cc2ccccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(NC)c(N=O)c2ccccn12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(methylamino)-3-indolizinecarboxylate 6 (4.45 g, 20.4 mmol) was dissolved in CH3COOH (40 mL) and cooled to 0° C., before a solution of sodium nitrite (1.7 g, 24.0 mmol) in water (10 mL) was added. After being stirred at 0° C. for 3 h, the reaction mixture was basified with a 2 M solution of NaOH (pH=8-9) and extracted with CH2Cl2 (3×50 mL). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residue was chromatographed on silica gel with an elution gradient of 1/1 to 4/1 of ethyl acetate/petroleum ether, to give, following removal of the solvents, 3.89 g of green microcrystals of ethyl 2-(methylamino)-1-nitroso-3-indolizinecarboxylate 7, m.p.: 156-157° C. 1H NMR (DMSO-d6): δ 1.40 (t, J=7.0 Hz, 3H), 3.47 (d, J=5.4 Hz, 3H), 4.38 (q, J=7.0 Hz, 2H), 7.35 (t, J=7.0 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.79 (br s, 1H), 8.38 (d, J=8.1 Hz, 1H), 9.27 (br s, 1H). 13C NMR (DMSO-d6): δ 14.5, 34.5, 59.7, 98.8, 116.2, 120.0, 123.5, 128.1, 135.2, 149.4, 149.8, 160.9.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[O:5]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(=O)c1c(C)cc(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
91 parts of 2,4,6-trimethylbenzoyl chloride are introduced into an apparatus as described in Example 1. 83 parts of triethyl phosphite are added in the course of 15 minutes at 60° C., after which the mixture is stirred for 8 hours at 80° C. The material discharged from the flask is distilled under a pressure of 0.4 mm and the fraction boiling at 120°-122° C. under this pressure is collected. 51 parts (36 percent of theory) of diethyl 2,4,6-trimethylbenzoylphosphonate are obtained as a pale yellowish liquid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([F:41])[CH:34]=1>>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:30]=2)=[CH:34][C:35]=1[F:41])#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: N#Cc1ccc(Br)cc1F
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C#N)c(F)c4)ccc3o2)CC1
Yield: 47.5 %

Procedure:
Following the General Procedure-2, the titled compound (70 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluorobenzonitrile (70 mg, 0.35 mmol) as a white solid. M.P.: 138-142° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.87 (d, J 1.6, 1H), 7.72-7.68 (m, 1H), 7.59 (d, J 8.5, 1H), 7.53-7.42 (m, 3H), 4.15 (d, J 10.6, 2H), 3.20-3.11 (m, 1H), 3.00 (t, J 11.8, 2H), 2.2-2.12 (m, 2H), 1.98-1.86 (m, 2H), 1.56 (S, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.O>C(O)CO>[CH2:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=2)[CH2:16][CH2:15]1)=[O:18])[CH3:21]
Reactant: CCc1cnc(Cl)nc1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: OCCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(Nc2ncc(CC)cn2)CC1
Yield: 46 %

Procedure:
A mixture of 2-chloro-5-ethylpyrimidine (5.0 g, 35.1 mmol, 1.0 equiv; commercially available), ethyl 4-amino-1-piperidine carboxylate (7.2 g, 42.1 mmol, 1.2 equiv) and triethylamine (5.3 g, 52.7 mmol, 1.5 equiv) in ethylene glycol (60 mL) was heated by microwave irradiation to 200° C. for 15 min. To the crude reaction mixture was added water (120 mL) and the solution extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (20 mL) and a sat. solution of sodium chloride (20 mL), dried over MgSO4 and evaporated under reduced pressure to give an amber oil. The residue was purified by column chromatography on silica eluting with heptane/ethyl acetate (1:1) followed by recrystallization from heptane (200 mL) to afford 4.53 g (46%) of the title compound as a white solid. MS (ISP): 279.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([NH2:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:15]1[C:27]2[NH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2C=CC=1.[Cl:28]C1C2C(=CC=CC=2)N=CC=1.CCOCC.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.O>[ClH:28].[N:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([NH:14][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:15][CH:27]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Clc1ccnc2ccccc12
Reactant: Nn1c2ccccc2c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: c1ccc2c(Nn3c4ccccc4c4ccccc43)ccnc2c1

Procedure:
A solution of 9H-carbazol-9-amine (11 g, as an unquantified mixture with carbazole) and 4-chloroquinoline (10 g) in 100 ml isopropanol acidified with ether/HCl was refluxed for seven hours, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed successively with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to 20 g solid. This material was converted to the hydrochloride salt in methanol/ether to give 6 g solid, m.p. >260°. Three grams were recrystallized from methanol/ether to give 2.6 g white needles, dec. 300°-302°.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:14]I>CN(C=O)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccnc2c1
Temperature: 0 °C
Yield: 99.7 %

Procedure:
A suspension of NaH (3.3 g; 137.93 mmol) in anhydrous DMF (160 ml) was cooled to 0° C. with stirring under argon. 7-Quinolinol (8 g; 55.17 mmol) dissolved in anhydrous DMF (320 ml) was added and the mixture was stirred at 0° C. under argon for 1 h. The mixture was then allowed to warm to rt and MeI (7.8 ml; 55.17 mmol) was added and the reaction was stirred for 1 h. Ice water was then added cautiously and the resulting mixture extracted with EtOAc (3×500 ml). The organic layer from this extraction was then washed with water (400 ml) and brine (400 ml). The resulting organic layer was dried with MgSO4 and solvents removed to afford the desired compound (8.76 g; 99%)
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH2:20][S:19][CH2:18][CH2:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>CO.O>[O:22]=[S:19]1[CH2:18][CH2:17][C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH2:20]1
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CSCC3
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CS(=O)CC3
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.3 g of 2,3,5,6,7,9-hexahydro-2-phenylthiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in 200 mL of methanol, a solution of 0.8 g of sodium metaperiodate in 25 mL of water is added. The mixture is stirred at room temperature for 48 hours, then evaporated to dryness. The residue is washed with 50 mL of water, filtered, and dried in a vacuum oven at 80° overnight obtaining 2,3,5,6,7,9-hexahydro-8-oxo-2-phenylthiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 218°-220° (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[C:3]1=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
3,3-Dimethyl-1,3-dihydro-indol-2-one (5.5 g, 34 mmol) was dissolved in dimethylformamide (50 mL) and sodium hydride (1.4 g, 38 mmol) was added portionwise and the mixture was stirred 30 minutes then benzyl bromide (4.8 mL, 41 mmol) was added. The mixture was stirred 2 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-20% ethyl acetate in hexane) to afford 7.1 g (83%) of 1-benzyl-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C-]#[N:9].[Na+].CN(C)[CH2:13][C:14](=O)[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:9][C:15]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1
Reactant: [C-]#N
Reactant: O=Cc1cccs1
Reactant: CN(C)CC(=O)Cc1cccs1
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1csc(-c2ccc(-c3cccs3)[nH]2)c1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 2-thiophene carboxaldehyde (6) in DMF is added under nitrogen to a suspension of sodium cyanide in DMF. The mixture is stirred and the 3-dimethylamino-1-(2-thienyl)-propanone (5) is added slowly. The mixture is allowed to stand overnight and the 1,4-Di-(2-thienyl)-1,4-butanedione product (7) is extracted with dichloromethane in 64% yield. 2,5,-Di-(2-thienyl)-pyrrole (DTP) can be produced in 80% yield by refluxing (7) for 12 hours with ammonium acetate in a mixture of acetic acid and acetic anhydride. The acid acts as a catalyst and the anhydride as a water scavenger which drives the equilibrium reaction towards the desired product. An N-substituted derivative of 2,5-DTP (9) may be produced by using an appropriate primary amine instead of ammonium acetate. The yield of (9) is often comparable to that of 2,5-DTP but does exhibit some dependence on the substituent group R; in particular, if R is bulky the yield may decrease substantially. Where appropriate, yields may be improved by the use of a benzene/acetic acid solvent system thus allowing the azeotropic removal of water from the reaction mixture by attaching a Dean-Stark trap. Alternatively, a stronger acid catalyst such as titanium (IV) chloride can be used.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[N:4][C:3]1=[O:10].[CH2:11]([Br:14])[CH:12]=[CH2:13]>C(#N)C>[Br-:14].[CH2:11]([NH+:4]1[C:5]([CH3:9])=[CH:6][CH:7]([CH3:8])[N:2]([CH3:1])[C:3]1=[O:10])[CH:12]=[CH2:13]
Reactant: Cc1cc(C)n(C)c(=O)n1
Reactant: C=CCBr
Solvent: CC#N
Product: C=CC[NH+]1C(=O)N(C)C(C)C=C1C
Product: [Br-]

Procedure:
A mixture of 8.0 g (0.058 mol) of 1,4,6-trimethylpyrimidin-2(1H)-one and 14.0 g (0.116 mol) of allyl bromide were heated together under reflux in acetonitrile for 16 hours under an inert gas atmosphere. After cooling, a violet solid precipitated out, which was filtered off with suction. The product was purified by recrystallization from chloroform/diethyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:26])=O.[BH3-]C#N.[Na+]>>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 41 %

Procedure:
Using a method similar to Example 204, using 6-S-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), acetone (116 mg, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (139 mg) as a white foam. Mass spectrum (ion spray): m/z=340 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.13 (d, 1H), 7.21-7.13 (m, 2H), 6.90-6.87 (m, 2H), 6.27 (br. s, 2H), 2.97 (m, 1H), 2.91-2.75 (m, 3H), 2.62-2.41 (m, 2H), 1.83-1.63 (m, 4H), 1.07 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.[CH2:17](N(CC)CC)[CH3:18].ClCC[C:27]12[CH2:35][CH2:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][NH:29][CH2:28]2>>[CH:31]12[CH2:32][CH2:33][CH:27]([CH2:35][CH2:34]1)[CH2:28][N:29]([CH2:17][CH2:18][N:11]1[CH2:12][CH2:13][C:8]3[C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=4[O:15][C:14](=[O:16])[C:9]=3[CH2:10]1)[CH2:30]2
Reactant: ClCCC12CCC(CC1)CNC2
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: CCN(CC)CC
Product: Cc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.009 moles), triethylamine (3.1 ml, 0.022 moles), and 3-(2-chloroethyl-3-azabicyclo[3.2.2]nonane. Recrystallization from ethanol gave the product (1.7 g), mp 155°-157° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3C(OC(C)(C)C)=O)=[O:15])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CCCCCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17]3)=[O:15])=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1C(=O)Nc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(-c2ccncc2)cc1)C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
To a suspension of N-[4-(4-pyridinyl)phenyl]-1-tert-butoxycarbonylindoline-2-carboxamide (100 mg) in ethyl acetate (0.60 mL) was added 4N hydrogen chloride-ethyl acetate (2.41 mL) and the mixture was stirred at ambient temperature for 1.5 hours. The resulting mixture was diluted with n-hexane (6.0 mL) and the solid was collected by filtration, and then washed with ethyl acetate/n-hexane (1:2, 1.0 mL) to give N-[4-(4-pyridinyl)phenyl]indoline-2-carboxamide (80 mg) as off-white crystals.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16].C([O-])(=O)C.[K+:23]>C(O)(=O)C>[K+:23].[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCS(=O)(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)[O-]
Yield: 77.6 %

Procedure:
Following the method described by Winterbottom, R. et al., J. Am. Chem. Soc., 69, 1393-1401 (1947), 21.4 g of phthalic anhydride (0.145 mol) were added to a suspension of taurine (17 g, 0.137 mol) and potassium acetate (14.2 g, 0.145 mol) in glacial acetic acid (48 mL), heated under reflux. Heating was continued to obtain the complete dissolution of the reagents (2.5 h); after cooling to 0°-5° C., a precipitate formed which was separated by filtration, washed with glacial acetic acid and absolute ethanol, dried in the air and under vacuum (50° C.), to give 31.2 g of 2-phthalimidoethanesulfonic acid potassium salt [m.p. >300° C.; 1H-NMR (D2O) d 7.85 (m, 4H), 4.05 (t, 3H, J=8 Hz), 3.25 (t, 2H, J=8 Hz). A suspension of 5 g of the salt in benzene (50 mL), dried by azeotropical distillation, was added with 2.56 g of phosphorous pentachloride (0.015 mol) and refluxed for 1 h. Then a second aliquot of phosphorous pentachloride (2.56 g, 0.015 mol) was added. The mixture was refluxed for a further 90 min, then solvents and reagents were evaporated off under vacuum and reduced pressure. The mixture was refluxed for a further 1.30 hours; cooled to r.t. and the solvents were evaporated under reduced pressure. The residue was taken up into 30 g of finely triturated ice to form a fine solid (which was filtered, washed with water and dried) of 2-phthalimidoethanesulfonyl chloride (3.71 g; m.p. =158-159° C.).
Reaction SMILES: Cl[CH:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1.[C:30]([O-:33])(=[O:32])[CH3:31].[K+]>C(O)(=O)C>[C:30]([OH:33])(=[O:32])[CH3:31].[OH:32][C@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1
Reactant: CC(=O)[O-]
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To the solution of 3-chlorocholest-5-en-24-one in glacial acetic acid (3 ml) was added anhydrous potassium acetate (0.2 g) and the solution was refluxed for 4 hours. The reaction mixture was concentrated and extracted with diethyl ether. The ether layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel to give 81.1 mg of 3β-hydroxycholest-5-en-24-one acetate having a melting point of 125°-127° C. after recrystallization from methanol.