Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH2:22][CH2:23][F:24].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[F:24][CH2:23][CH2:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccncc1B(O)O
Reactant: O=[N+]([O-])c1ccc(Br)c(OCCF)c1
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: Cc1ccncc1-c1ccc([N+](=O)[O-])cc1OCCF

Procedure:
Intermediate 16C was prepared from Intermediate 1A and Intermediate 16B by the procedure described for the preparation of Intermediate 1C, and was obtained as a beige solid (254 mg, 61% yield). MS (ES): m/z=277.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)c1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-methoxybenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and m-anisoyl chloride in a similar manner as described above to give an orange solid (49% yield). 1H-NMR (CDCl3): δ 8.92 (s, 1H), 7.61 (m, 1H), 7.38-7.30 (m, 2H), 7.30-7.25 (m, 1H), 7.23 (m, 1H), 7.17 (d, 1H), 7.08-7.02 (m, 1H), 6.39 (d, 1H), 5.32 (m, 1H), 3.85 (s, 3H), 2.72 (m, 2H), 2.31 (m, 1H), 1.97 (m, 3H); MS m/z 399 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]3)[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18](O)=[C:17]([O:24][CH3:25])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Cl.[CH2:47]([N:49]([CH2:52][CH2:53]Cl)[CH2:50][CH3:51])[CH3:48]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]3)[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:48][CH2:47][N:49]([CH2:52][CH3:53])[CH2:50][CH3:51])=[C:17]([O:24][CH3:25])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CCCl
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCc1c(OC)cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1OC
Reaction time: 24 h

Procedure:
Combine 1-[2-[3-(3,4-dichloro-phenyl)-1-(3,5-dimethoxy-4-hydroxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid amide (1 mmol) and sodium hydride (2 mmol) in tetrahydrofuran (10 mL). Add diethylaminoethylchloride hydrochloride (1 mmol). After 24 hours, partition the the reaction mixture between water and ethyl acetate. Separate the organic layer, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1([CH2:22][CH:23]=C)[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1=[O:21])[CH:2]=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCCl>[CH3:20][Si:17]([CH3:18])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:4]2([CH2:1][CH:2]=[CH:23][CH2:22]2)[C:5]1=[O:21]
Reactant: C=CCC1(CC=C)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCN1C(=O)C2(CC=CC2)c2cccnc21

Procedure:
A mixture of 3,3-diallyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one from Step A (1.02 g, 2.96 mmol) and Grubbs second generation catalyst (37 mg, 0.045 mmol) in DCE (60 mL) was heated at reflux for 3.5 h. The mixture was concentrated in vacuo and purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[CH:6]=1)[CH3:3].CS[C:17]1[N:22]=[C:21]([OH:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>C(O)C>[N+:24]([C:20]1[C:21](=[O:23])[NH:22][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:7]2[CH:6]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:9][CH:8]=2)=[N:18][CH:19]=1)([O-:26])=[O:25]
Reactant: CN(C)Cc1cc(CSCCN)cs1
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Solvent: CCO
Product: CN(C)Cc1cc(CSCCNc2ncc([N+](=O)[O-])c(=O)[nH]2)cs1
Yield: 63.5 %

Procedure:
A mixture containing 2-[(5-dimethylaminomethyl-3-thienyl)methylthio]ethylamine (2.88 g; 12.5 mmoles) and 2-methylthio-5-nitro-4-hydroxypyrimidine (2.33 g; 12.44 mmoles) in 10 ml of ethanol was heated at reflux temperature for 13 hours. The reaction mixture was evaporated under reduced pressure, and the residue was placed on 150 g of silica gel and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride. The appropriate fractions gave 2.92 g of product which was recrystallized from tetrahydrofuran to give the title compound, mp 150°-153° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].CN1C(=O)CCC1.[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: CC(C)C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccnc(CC(C)C)c1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-isonicotinic acid ethyl ester (10.0 g, 63.3 mmol) in THF (150 mL), NMP (8.78 g, 88.6 mmol) and Fe(acac)3 (2.46 g, 6.96 mmol) is added under argon. The mixture is cooled to −74° C. before isobutylmagnesium bromide (47 mL of a 2 M solution in THF, 94.9 mmol) is added. The temperature rises to −65° C. The mixture is stirred at −75° C. for 1 h, then warmed to rt and carefully quenched with water. The mixture is extracted with EA, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-isobutyl-isonicotinic acid ethyl ester (3.00 g) as an oil, LC-MS: tR=0.74 min, [M+1]+=208.11.
Reaction SMILES: C(O)CCCCCCC#C.[CH2:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22]>NCCCN>[CH2:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CCC#CCCCCCCCCO
Agent: C#CCCCCCCCO
Agent: NCCCN
Product: C#CCCCCCCCCCCO

Procedure:
The same procedure for 8-nonyn-1-ol was followed with 9-dodecyn-1-ol (4.68 g, 25.7 mmol), KH(3.09 g, 77.0 mmol), and 1,3-diaminopropane (70 mL). This produced 4.33 g of yellow oil (93%): IR (neat) ν 3317,2930, 2121 cm−1; 1H—NMR δ 3.62 (t, 2H, J=6.6 Hz), 2.17 (td, 2H, J=2.6 Hz, 7.1 Hz), 1.93 (t, 1H, J=2.6 Hz), 1.76 (bs, 1H), 1.55 (m, 4H), 1.28 bm, 12H); 13C—NMR δ 84.8, 68.0, 63.0, 32.7, 29.5, 29.4 (2C), 29.0, 28.7, 28.4, 25.7, 18.4; MS m/z 189.18 (M++Li).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH:16]=[O:17])[CH:12]=[CH:11][C:10]=1[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH2:21]([S:18]([C:10]1[CH:11]=[CH:12][C:13]([NH:15][CH:16]=[O:17])=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8])(=[O:20])=[O:19])[CH3:22]
Reactant: CCS(=O)(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(NC=O)cc1S(N)(=O)=O
Yield: 65.6 %

Procedure:
3.0 g of N-tert-butyl-2-ethylsulfonyl-5-formylaminobenzenesulfonamide are stirred in 20 ml of trifluoroacetic acid. When the reaction has ended, the trifluoroacetic acid is distilled off. The residue is stirred with a little ethyl acetate. After the solid has been separated off and dried, 1.65 g of the desired sulfonamide are obtained; melting point: 186° to 189° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN1CCCC1=O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([O:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:4]2[CH:3]=[C:2]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][CH2:23][N:29]3[C:33](=[O:34])[C:32]4[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:30]3=[O:39])[CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:18]1
Reactant: C#CCCCCN1C(=O)c2ccccc2C1=O
Reactant: CN1CCC(OC(c2cccc(I)c2)c2ccccn2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCC(OC(c2cccc(C#CCCCCN3C(=O)c4ccccc4C3=O)c2)c2ccccn2)CC1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A screw-cap tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]pyridine (105 mg, example 37), tetrakis(triphenylphosphine)palladium (52 mg), copper(I) iodide (26 mg), N-5-hexynylphthalimide (186 mg), triethylamine (400 μL) and 1-methyl-2-pyrrolidinone (4 mL). The tube is evacuated, filled with argon and sealed. After stirring at 90° C. for 14 h, the mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5) to give 2-(6-{3-[(1-methylpiperidin-4-yloxy)-pyridin-2-ylmethyl]phenyl}hex-5-ynyl)isoindole-1,3-dione as an brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][C:6](=[O:8])[CH:5](C(OCC)=O)[C:4](=[O:14])[CH2:3]1>C(#N)C.O>[CH3:1][C:2]1([CH3:15])[NH:7][C:6](=[O:8])[CH2:5][C:4](=[O:14])[CH2:3]1
Reactant: CCOC(=O)C1C(=O)CC(C)(C)NC1=O
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(=O)CC(=O)N1
Yield: 84.9 %

Procedure:
Ethyl 6,6-dimethyl-2,4-dioxopiperidine-3-carboxylate (0.69 g, 3.23 mmol) was dissolved in acetonitrile containing 1% of water (15 mL) and the resulting solution was refluxed for 2 hours. After evaporating to dryness, the crude material was suspended in isopropyl ether, kept under vigorous stirring and filtered to give the title compound (387 mg, Y=85%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15](I)=[CH:16][C:9]=23)[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.COCCOC.C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH:29]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(I)cc12
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C1CC=C(c2cc3c(-c4cc(F)ccc4OC)ccnc3[nH]2)CC1
Temperature: 100 °C

Procedure:
To a solution of Example 219A (500 mg, 1.358 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (495 mg, 1.766 mmol), and bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.136 mmol) in 30 mL 7:2:3 1,2-dimethoxyethane/ethanol/water was added sodium carbonate (432 mg, 4.07 mmol). The mixture was heated at 100° C. for 4 hours, cooled to room temperature, and diluted with 50 mL ethyl acetate. The mixture was washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ethyl acetate and the solid was filtered and dried in vacuo to give the title compound. MS (ESI): 395.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([S:27]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
tert-Butyl piperidin-4-ylmethylcarbamate (0.100 g) in dichloromethane (2.3 mL) was treated with 5-(pyridin-2-yl)thiophene-2-sulfonyl chloride (0.133 g), followed by triethylamine (0.325 mL) at room temperature. After stirring the mixture at room temperature overnight, it was washed with 1N hydrochloric acid, the organic layer was separated and filtered. Evaporation of the solvent and purification by column chromatography on silica gel (1-4% methanol in dichloromethane) provide the title compound (0.088 g) having the following physical data.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[Br:9][C:10]1[N:11]=[C:12]([C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[N:25]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:24]3=[O:40])=[O:20])[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12>CN(C=O)C>[Br:9][C:10]1[N:11]=[C:12]([C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:1])[C:26](=[O:31])[N:25]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:24]3=[O:40])=[O:20])[N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12
Reactant: O=C(c1ccc2[nH]c(=O)n(Cc3ccc(F)cc3)c(=O)c2c1)c1nc(Br)c2ccccn12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)n(Cc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
1.87 g (5.7 mmol) of caesium carbonate and 0.39 ml (6.2 mmol) of methyl iodide are added, at ambient temperature under an inert atmosphere, to 2.6 g (5.17 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)quinazoline-2,4(1H,3H)-dione in 50 ml of anhydrous DMF. The reaction medium is stirred for 18 hours at ambient temperature and then filtered. The precipitate is rinsed with water and then dried under reduced pressure at 50° C. overnight. 2.54 g of a yellow solid are obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.[N+:19]([O-:22])([OH:21])=[O:20].CC1([C:30]([NH2:32])=[NH:31])C=C(C)N=N1>C(O)C>[N+:19]([O-:22])([OH:21])=[O:20].[C:30]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[NH:31])[NH2:32]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: CC1=CC(C)(C(=N)N)N=N1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Yield: 42.9 %

Procedure:
A solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (4.2 g), 3,5-dimethylpyrazole carboxamidine nitrate (3.6 g) in 95% ethanol (80 ml) is heated under reflux for 7 hours. The mixture is evaporated to dryness in vacuo and the viscous residue is triturated with ether. After filtration, the precipitate is twice recrystallized from ethyl acetate/methanol to yield product (2.6 g, 42%) as a solid, mp 188°.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:28].[Na+].[Na+]>S(=O)(=O)(O)O>[C:13]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][CH2:10][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])[C:25]([NH2:26])=[O:28])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: CN(CCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(CCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenylpropane (11.1 g--see Preparation 5) in 90% sulphuric acid (66 ml) was heated at 100° for 1 hour. The mixture was allowed to cool to room temperature and poured into ice/water (300 ml). The aqueous mixture was basified with saturated aqueous sodium carbonate and extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound, yield 10.6 g. A sample recrystallised from ethanol had a melting point of 145°-148°.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])=[CH:15][CH:14]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])=[CH:17][CH:18]=1
Reactant: Nc1ccccc1-c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1ccccc1-c1ccc(Br)cc1
Yield: 97.8 %

Procedure:
Add DBU drop wise (8.76 mL, 56.92 mmol) to a solution of 2-(4-bromophenyl)phenylamine (3.53 g, 14.23 mmol) in methylene chloride (50 ml) at 0° C., followed by isopropylsulfonyl chloride (3.29 mL, 28.46 mmol) also added drop wise and stir the reaction at room temperature for 24 h. Remove solvent under reduce pressure and purify the residue by silica gel chromatography eluting with ethyl acetate:hexane 1:4 to ethyl acetate to provide the title compound (4.93 g, 98%). Mass spectrum (m/e): 355 (M+1); 353 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[O:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])C.OC1C=CC(C)=CC=1C(C1C=CC=CC=1)=O.C(OCC)(=O)CC(OCC)=O.N12CCCN=C1CCCCC2.Cl>C(O)(=O)C>[CH3:22][C:19]1[CH:20]=[CH:21][C:9]2[O:8][C:7](=[O:23])[C:6]([C:4]([OH:5])=[O:3])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[CH:18]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(C)ccc2oc1=O
Agent: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: CCOC(=O)CC(=O)OCC
Product: Cc1ccc2oc(=O)c(C(=O)O)c(-c3ccccc3)c2c1
Temperature: 110 °C

Procedure:
A mixture of 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid ethyl ester [prepared by heating 2-hydroxy-5-methylbenzophenone and diethyl malonate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-en; melting point: 129°-131° C.; NMR (200 MHz, CDCl3) ppm: 0.96 (3H, t, J=7.2 Hz), 2.31 (3H, s), 4.07 (2H, q, J=7.2 Hz), 7.01 (1H, bs), 7.2-7.4 (4H, m), 7.5-7.6 (3H, m)] (10.0 g), acetic acid (100 ml). and hydrochloric acid (60 ml) was heated under reflux at 110° C. for 15 hours. After the solvent was distilled off, ethyl acetate was added to the residue. The mixture was washed with water and dried, after which the solvent was distilled off, to yield 6-methyl-2-oxo-4-phenyl-2H-1-benzopyran-3-carboxylic acid as colorless crystals (8.7 g).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[C:35]1([CH2:41][CH:42]=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:35]1([CH:41]([N:3]2[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:14][CH2:15]3)[CH2:4]2)[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(c1ccccc1)N1CCC[C@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C

Procedure:
Benzyl 4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxylate dihydrochloride (1.5 g) was suspended in THF (45 ml) and stirred at room temperature. N,N-Diisopropylethylamine (3.3 ml) was added followed by phenylacetaldehyde (0.9 ml) and magnesium sulphate (300 mg). After 20 minutes sodium triacetoxyborohydride (1.6 g) was added and stirring continued overnight. Inorganic residues were removed by filtration and the filtrate was adsorbed onto silica for purification by chromatography eluting with 0-7% methanol/dichloromethane. This gave benzyl 4-{[(3R)-1-phenylethylpiperidin-3-yl]methyl}piperazine-1-carboxylate as a pale yellow gum (960 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]1[NH:13][C:14]2[C:15]([N:36]=1)=[CH:16][C:17]1[C:18]([CH3:35])([CH3:34])[C:19](=[O:33])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[O:31][CH3:32])[C:21]=1[CH:22]=2.CCN(C(C)C)C(C)C.N1CCCCC1>C1COCC1.CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:20]2[C:21]3[CH:22]=[C:14]4[NH:13][C:12]([NH:11][C:5](=[O:6])[C:4]5[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=5)=[N:36][C:15]4=[CH:16][C:17]=3[C:18]([CH3:35])([CH3:34])[C:19]2=[O:33])=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: COc1cc(F)ccc1CN1C(=O)C(C)(C)c2cc3nc(N)[nH]c3cc21
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(F)ccc1CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4cccc(C)c4)[nH]c3cc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 10.6 %

Procedure:
To a solution of 3-methyl-benzoyl chloride (62 mg) in THF (2 ml) is added D9 (35.4 mg) and DIPEA (30 μl). The reaction mixture is stirred at 50° C. for 12 h. Afterwards MeOH (1 ml) and piperidine (100 μl) are added. After shaking for 2 h the mixture is evaporated to dryness and purified by preparative RP-HPLC, eluted with MeCN/water to give the desired product (5 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[NH:5][N:4]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28]C)=[O:27])=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(CC)n[nH]1
Product: CCCCc1nc(CC)nn1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 10.1 %

Procedure:
Following General Procedure A, 1.0 g (6.0 mmol) of 3-ethyl-5-butyl-1H-1,2,4-triazole was reacted with 2.41 g (7.9 mmol) of the alkylating reagent prepared in step 1 of Example 1. Hydrolysis of the faster moving isomer provided 220 mg of 4′-[(3-ethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ 0.85 (t, J=7 Hz, 3H), 1.19 (t, J=7 Hz, 3H), 1.27–1.38 (m, 2H), 1.52–1.63 (m, 2H), 2.59 (q, J=7 Hz, 2H), 2.74 (t, J=7 Hz, 2H), 5.35 (s, 2H), 7.21 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H), 7.35 (dd, J=8 and 2 Hz, 1H), 7.48 (dt, J=8 and 2 Hz, 1H), 7.57 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H).