Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:12]1([CH2:11][CH2:10][C:9]2([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCO
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(CCC2(CCc3ccccc3)OCCO2)cc1

Procedure:
A solution of 135 mg (0.6 mmol) of 1,5-diphenyl-3-pentanone, 0.2 ml of ethylene glycol, and 10 mg of p-toluene sulfonic acid monohydrate was refluxed with azeotropic removal of water. After separation of water was completed, the solution was diluted with ethyl acetate, washed sequentially with aqueous NaHCO and water, dried over Na2SO4, and concentrated to provide the desired compound. 1H NMR (CDCl3) δ 2.0 (m, 4H), 2.71 (m, 4H), 4.03 (s, 4H), 7.15-7.3 (m, 10H). Mass spectrum: (M+H)+ =283.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:20])[NH:10][C:11]3[C:16]=2[CH:15]=[C:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([O:20][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH2:15][C:14]3=[CH:17][CH:18]=[CH:19][C:13]3=[CH:12][C:11]=2[N:10]=1)[CH3:29]
Reactant: O=c1[nH]c(-c2ccccc2)c2cc3cccc3cc2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(c(-c3ccccc3)n1)CC1=CC=CC1=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a suspension of 4-phenylcyclopenta[g]quinazolin-2(1H)-one (120 mg, 0.46 mmol) and K2CO3 (76 mg, 0.55 mmol) in 4 mL of DMF was added iodoethane (44 μL, 0.55 mmol) and stirred at rt overnight. Water was then added and the resulting suspension extracted with 2×20 mL of EtOAc. The extract was washed with water twice and brine, then dried over MgSO4 and concentrated in vacuo. The crude solid was then subjected to flash column chromatography eluting with acetone/hexane to give the title compound 2-ethoxy-4-phenyl-cyclopenta[g]quinazoline (25 mg, 19%) followed by the title compound 1-ethyl-4-phenylcyclopenta[g]quinazolin-2(1H)-one (66 mg, 50%). 1H NMR (CDCl3): 7.7 (d, 2H), 7.63 (s, 1H), 7.53 (m, 3H), 7.29 (s, 1H), 4.38 (q, 2H), 3.09 (t, 2H), 2.93 (t, 2H), 2.16 (p, 2H), 1.45 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: COCCOc1c(Br)cc(C(O)c2ccccc2)cc1OC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOc1c(Br)cc(Cc2ccccc2)cc1OC
Reaction time: 2 h
Yield: 77 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and a nitrogen inlet was added of 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol (12.83 g, 34.94 mmol), dry methylene chloride (200 mL) and triethylsilane (13.87 mL, 87.34 mmol). This solution was cooled in an ice bath and borontrifluoride etherate (4.43 mL, 34.94 mmol) was added with a syringe over 5 min. The mixture was aged 2 h at 0° C. The reaction was quenched with saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform. The chloroform fraction was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This material was chromatographed on 400 g of silica gel using 20/80 EtOAc-hexane as eluant to give 9.45 g of 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethane as an oil. 1H NMR (CDCl3): δ3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.77 (s, 3H); 3.88 (s, 2H); 4.13 (t, j=4 Hz, 2H); 6.64 (d, j=2Hz, 1H); 6.94 (d, j=2Hz, 1H); 7.26 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Cl[C:13]1[C:14]2[C:21]([C:22]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)=[O:23])=[CH:20][NH:19][C:15]=2[N:16]=[CH:17][N:18]=1>>[C:24]1([C:22]([C:21]2[C:14]3[C:13]([NH:1][C:2]4[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=4)[C:5]([NH:7][CH3:8])=[O:6])=[N:18][CH:17]=[N:16][C:15]=3[NH:19][CH:20]=2)=[O:23])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ncnc(Cl)c12
Product: CNC(=O)c1cccc(Nc2ncnc3[nH]cc(C(=O)c4cccc5ccccc45)c23)c1

Procedure:
3-((5-(1-Naphthoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-methylbenzamide was synthesized using 3-amino-N-methylbenzamide and (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(naphthalen-1-yl)methanone according to the general procedure A. A yellow solid was obtained. M.p.>300° C.; 400 MHz 1HNMR (DMSO-d6) δ 11.53 (s, 1H), 8.48-8.44 (m, 2H), 8.24-8.20 (m, 2H), 8.14 (d, J=8.0 Hz, 1H), 8.06-8.03 (m, 2H), 7.80-7.78 (m, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.64-7.53 (m, 3H), 7.50-7.44 (m, 2H), 2.77 (d, J=4.4 Hz, 3H); LCMS [M+H] 422.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH:11]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH2:17][CH2:16]2)=[O:14])[N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]1[CH2:9][N:10]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:11]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])[CH2:19][CH2:20]2)=[O:14])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 102.7 %

Procedure:
{1-Benzyl-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidine-3-yl}carbamic acid tert-butyl ester (2 g, 4 mmol) was dissolved in 15 mL DCM/CF3COOH (2:1), stirred overnight. After removal of solvent, the residue was treated with saturated NaHCO3, extracted with EA (2×100 mL). The organic layer was dried over Na2SO4, concentrated to afforded title product 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile 1.6 g (100%) as brown oil. MS m/e=390.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13](N)([NH2:16])(=[O:15])=[O:14]>O1CCOCC1>[NH2:16][S:13]([N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
4-Phenyl-piperidine (10 g, 62 mmol) was dissolved in dioxane (100 mL). Sulfamide (23.8 g, 248 mmol) was then added and the reaction mixture heated to 100° C. for 14 h. The reaction mixture was then cooled to room temperature, quenched by addition of 1N HCl and then concentrated to remove dioxane. The product was extracted with ethyl acetate (100 mL), dried (Na2SO4), filtered and concentrated to yield the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)c(N3CCN(c4ccncc4)CC3)cn(Cc3ccccc3)c2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=c1c(N2CCN(c3ccncc3)CC2)cn(Cc2ccccc2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 336 h
Yield: 9.5 %

Procedure:
To a solution of the product of step (vi) (815 mg) in dry dichloromethane (10 ml) under argon was added a 1M solution of boron tribromide in dichloromethane (10 ml). The reaction was stirred at room temperature for 14 days, extra aliquots of BBr3 solution being added after 3 and 7 days. After 2 weeks, excess 1M aqueous sodium hydroxide solution was added, dropwise at first, and the mixture stirred at room temperature for 3 hours. The precipitated material was filtered off and the aqueous layer of the filtrate separated. The pH of the aqueous layer was adjusted to 8 by addition of 2N HCl (aq.) and 1M NaHCO3 (aq.) before being extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness to yield 1-benzyl-3-(4-(4-pyridyl)piperazin-1-yl)-4-quinolon-7-ol (75 mg) as an off-white solid: m.p. 141°-6° C. NMR (d6DMSO) δ3.10 (4H, m), 3.50 (4H, m), 5.40 (2H, s), 6.67 (1H, d), 6.72 (1H, dd), 6.90 (2H, m), 7.30 (5H, m), 7.76 (1H, s), 8.07 (1H, d), 8.15 (2H, s), 10.15 (1H, br, s); m/Z 413 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH:28]3[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A solution of 4′-(methylsulfonyl)-4-biphenylol (0.15 g, 0.60 mmol), N-Boc-4-piperidinemethanol (0.14 g, 0.60 mmol) and Ph3P (0.16 g, 0.66 mmol) in THF (4 mL) was cooled to −20° C. Diisopropyl azodicarboxylate (0.13 g, 94%, 0.60 mmol) in THF (1 mL) was added dropwise. The reaction mixture was kept between −20° C. and 0° C. for 3 h, then allowed to warm up to ambient temperature, and stirred at ambient temperature overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by chromatography on a silica gel column eluted with 40% EtOAc/hexane to give 0.20 g (74%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.97 (d, 2H, J=7.6 Hz), 7.83 (d, 2H, J=7.3 Hz), 7.64 (d, 2H, J=7.6 Hz), 7.03 (d, 2H, J=7.8 Hz), 4.15-4.05 (m, 2H), 3.90 (d, 2H, J=6.4 Hz), 3.13 (s, 3H), 2.90-2.70 (bs, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 446 (M+H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20]([C:22](=O)[CH3:23])[CH:21]=1>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20](/[C:22](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:23])[CH:21]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(N)(=O)=O)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(N)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 40.5 %

Procedure:
3-(hydrazinecarbonyl)benzenesulfonamide (50 mg, 0.232 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.6 mg, 0.232 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)benzenesulfonamide (36 mg, 0.094 mmol, 40.4% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.34 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.73 (t, 1H, J=8.0 Hz), 7.64 (m, 1H), 7.51 (bs, 2H), 7.32 (dd, 1H, J=2.4 & 8.4 Hz), 6.92 (d, 1H, J=8.4 Hz), 2.49 (s, 3H). Mass [M+H]+: 368.0
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:19]1[S:21][CH2:20]1>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:19][CH2:20][SH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C1CS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: SCCC1c2ccccc2-c2ccccc21
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
A solution of fluorene (20.0 g; 120 mmol) in THF (200 mL) was cooled to -40° C. and treated with 48 mL of a 2.5M solution of n-butyllithium in hexanes (120 mmol). After stirring for 15 minutes, a solution of ethylene sulfide (6.5 mL; 109 mmol) in 30 mL of THF was added, and the resulting mixture was stirred at -40° C. for 30 minutes and room temperature for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride, the layers were separated, and the organic phase was washed with 10% HCl, dried and concentrated. The crude product was purified on a flash column, eluting with hexane, to provide 16.8 g (62%) of the product as an oil that recrystallized from hexane as a white solid, mp 38°-40° C.
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:21]1(N)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)C>CO>[CH:21]1([NH:20][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:16]=3[N:17]=[CH:18][N:19]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 6-chloroadenosine (43 g) and cyclopentylamine (5 eq.) in ethanol (50 eq.) was heated at reflux for 3 hours then cooled to room temperature. The resultant reaction mixture was concentrated in vacuo and the resultant residue was diluted with water (400 ml) and ethyl acetate (400 ml). The eoganic layer was separated and the aqueous layer was extracted into ethyl acetate (2×400 ml). The combined organic layers were washed with water (2×200 ml), dried over sodium sulfate, concentrated in vacuo and dried under vacuum to provide a solid which was suspended in MeOH (400 mL), filtered and dried to provide N6-cyclopentyladenosine (43.8 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:30]1([C:33]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:15]=[CH:16][C:17]=2[CH3:18])[N:5]=3)=[O:34])[CH2:32][CH2:31]1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of benzyl {3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}carbamate (25.1 g, 61.9 mmol) in pyridine (200 mL) was added cyclopropanecarbonyl chloride (9.47 mL, 105 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Methanol (100 mL) and potassium carbonate (8.55 g, 61.9 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, and washed successively with methanol (200 mL), water (100 mL), methanol (100 mL) and hexane (100 mL) to give the title compound (23.9 g, 81%) as a white solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[C:12]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCc1cc(F)cc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCc1cc(F)c(B(O)O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of n-butyllithium (10.4M in hexane; 2.70 ml, 0.028 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 13 (5.00 g, 0.027 mol) in dry THF (60 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and a previously cooled solution of tri-isopropyl borate (10.22 g, 0.054 mol) in dry THF (50 ml) was added dropwise at -78° C. The stirred mixture was allowed to warm to room temperature overnight and stirred for 1 h with 10% hydrochloric acid (30 ml). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to give a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)=[O:27])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: N#Cc1cc(Br)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N#Cc1cc(Br)ccc1NC(=O)c1ccccn1
Yield: 70.9 %

Procedure:
To a stirred solution of 2-amino-5-bromobenzonitrile 2-1 (2.8 g, 0.014 moles) in toluene was added (4.95 mL, 0.028 moles) of N,N-diisopropylethylamine, followed by slow addition of (2.74 g, 0.015 moles) picolinoyl chloride. The mixture was stirred until complete by TLC. Reaction was filtered and dried under vacuum to afford 3 grams of 2-2. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 95% pure, M+1 peak m/e 301.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:24])[N:14]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:15]3=[N:16][C:17]=2[CH:18]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH:28]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:24])[N:14]3[CH2:23][CH2:22][N:21]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[CH2:20][CH2:19][C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: O=CCC(F)(F)F
Reactant: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CCNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CCN(CCC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2-(pyridin-2-yl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (150 mg, 0.48 mmol), 3,3,3-trifluoropropanal (80 mg, 0.72 mmol), and sodium cyanoborohydride (60 mg, 0.96 mmol) in MeOH (10 mL) was added acetic acid (29 mg, 0.48 mmol). The mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with saturated sodium carbonate solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the desired product. The product was then converted to the corresponding 2HCl salt. MS (ESI): 413 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.94-8.92 (d, J=5.82 Hz, 1H), 8.72-8.66 (t, J=7.98 Hz, 1H), 8.39-8.34 (t, J=9.00 Hz, 2H), 8.15-8.10 (t, J=7.83 Hz, 1H), 8.07 (s, 1H), 7.91-7.88 (d, J=8.22 Hz, 1H), 4.84-4.80 (m, 3H), 3.81-3.71 (m, 5H), 3.66-3.54 (m, 2H), 3.03-2.94 (m, 2H). mGluR5 PAM EC50: ++. Fold shift at 10 μM: +++.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:23][C:8]2=[N:9][CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[C:7]2[CH:6]=1)=[O:4]>[Fe]>[CH3:1][O:2][C:3]([C:5]1[O:23][C:8]2=[N:9][CH:10]=[CH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[C:7]2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2o1
Agent: [Fe]
Product: COC(=O)c1cc2c(Oc3ccc(N)cc3)ccnc2o1
Yield: 86.9 %

Procedure:
4-(4-Nitrophenoxy)-furo[2,3-b]pyridine-2-carboxylic acid methyl ester (70 mg) was subjected to iron reduction by the same method as in Production Example 10 to obtain the title compound (55 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:10]([CH2:11][C:12](=[O:27])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](OCC)=[O:29].[O-]CC.[Na+]>C1COCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH:14]([CH2:13][C:12](=[O:27])[C:11]2=[CH:28][OH:29])[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(=O)C(=CO)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
9-(4-Chloro-benzenesulfonyl)-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (5.08 g, 12.2 mmol) was dissolved in THF/ethanol (40 mL, 1/1, v/v). Ethyl formate (9.84 mL, 122.4 mmol) was added followed by sodium ethoxide (12 mL of 21% solution in ethanol). The resulting mixture was stirred at room temperature for 30 minutes then heated to 60° C. for 30 minutes after which the solution was cooled back to room temperature and quenched by the addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 5.43 g (quantitative) of 9-(4-chloro-benzenesulfonyl)-6-hydroxymethylene-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=2.114, method [1], MS (ESI) 465.0 (M+Na).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].ClC1[N:14]=[C:13]2[CH:15]([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17]C2=CC=1>CO>[O:1]=[C:5]1[NH:14][C:13]2[CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:2]=2[CH:3]=[CH:4]1
Reactant: COC(=O)C1CCc2ccc(Cl)nc21
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCc2ccc(=O)[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a 15 mL mixture of tetrahydrofuran, methanol, and a 1.0 N aqueous LiOH solution in a 3:1:1 ratio was added 0.242 g (1.14 mmol) of methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate from Step C above. The resulting mixture was stirred at ambient temperature for 1 h. The solution was evaporated in vacuo and the resulting light brown residue was purified by reverse phase HPLC (YMC Pack Pro C18, 100×20 mm I D column, 0-60% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in water gradient) to give the title compound as a brown oil (184 mg, 90%). LC-MS: m/z (E/S) 180.0 (MH)+.