Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.Cl[C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]=[O:33]>O1CCCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:34]([CH3:35])[C:29]2[S:30][C:31]([C:32]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:4][CH:3]=3)=[O:33])=[CH:27][N:28]=2)=[CH:38][CH:39]=1
Reactant: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)c1ncc(C(=O)c2c[nH]c3ncccc23)s1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to −10° C. in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H+]+=575.29.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:21]1([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cccc(-c2ccccn2)c1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: c1ccc(Nc2cccc(-c3ccccn3)c2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
2-(3-bromophenyl)pyridine (4 g, 17.09 mmol), Pd2(dba)3 (0.156 g, 0.171 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (S-Phos) (0.281 g, 0.683 mmol), and sodium t-butoxide (2.463 g, 25.6 mmol) were mixed in 100 mL of xylene. The solution was bubbled with nitrogen for 20 min. Aniline (2.387 g, 25.6 mmol) was added. The reaction was heated up to reflux for 6 h. After cooled to rt, dichloromethane was added. The mixture was filtered through Celite®. The solvent was then evaporated. The residue was coated on Celite® and columned with 1:5 hexanes/ethyl acetate to give N-phenyl-3-(pyridin-2-yl)aniline (3.6 g, 14.62 mmol, 86% yield) as light yellow solid.
Reaction SMILES: CCC.[OH:4][C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1.[Cl:11][CH2:12][CH2:13]O>O.[Cl-].[Zn+2].[Cl-]>[Cl:11][CH2:12][CH2:13][O:4][C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1
Reactant: OCCCl
Reactant: N#CC1(O)CCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCC
Product: N#CC1(OCCCl)CCC1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
Zinc chloride (36.03 g, 264 mmol) was fused using a propane torch while under vacuum. The molten salt was cooled and the evacuated flask was flushed with nitrogen. The flask was loaded with 1-hydroxycyclobutanecarbonitrile (15.10 g,) and 2-chloroethanol (17.7 g, 218 mmol) and stirred with heating (90° C.) for 20 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (1×150 mL, 4×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to an oil in-vacuo. The crude product was purified by vacuum distillation (b.p.12 85° C.) to give title compound (5.00 g, 31.3 mmol, 16.4% over two steps) as a clear liquid. 1H NMR (500 MHz, CDCl3) δ: 3.75 (2H, t, J=5.5 Hz), 3.65 (2H, t, J=5.6 Hz), 2.52-2.61 (2H, m), 2.31-2.43 (2H, m), 1.91-2.06 (2H, m).
Reaction SMILES: CC1C=CC(S([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=4)[N:23]=3)[CH:15]=[CH:16]C=2)(=O)=O)=CC=1.ClC1C=CC2N(C=C(NC(=O)C)N=2)N=1.[F:45]C1C=C(B(O)O)C=CN=1>>[F:45][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[N:26]=3)[N:23]=2)[CH:15]=[CH:16][N:11]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Agent: CC(=O)Nc1cn2nc(Cl)ccc2n1
Product: CC(=O)Nc1cn2nc(-c3ccnc(F)c3)ccc2n1

Procedure:
Following the procedure described for N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.040 g, 0.19 mmol) was reacted with 2-fluoropyridin-4-ylboronic acid (0.054 g, 0.38 mmol, Synthonix, Wake Forest, N.C.) to afford the title compound as a yellow solid. MS (ESI positive ion) m/z: 272 (M+1). 1H NMR (400 MHz, DMSO-d6): δ pp, 11.00 (s, 1H), 8.43 (d, J=5.3 Hz, 1H), 8.18 (d, J=10.0 Hz, 1H), 8.05 (t, J=1.6 Hz, 0.5H), 8.04 (t, J=1.6 Hz, 0.5H), 7.96 (d, J=9.4 Hz, 1H), 7.86 (s, 1H), 2.13 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([CH2:14]Br)[CH2:13][CH2:12]1>CN(C=O)C>[CH:11]1([CH2:14][O:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 28.8 %

Procedure:
To a cold solution of 2-hydroxy-5-nitro pyridine (0.500 g, 3.57 mmol) in DMF (4.0 mL) was added cyclopropyl methyl bromide (0.481 g, 3.57 mmol) at 0° C. The reaction mass was stirred at RT for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.200 g of the desired product. 1HNMR (DMSO-d6): δ 0.45-0.48 (m, 2H), 0.70-0.75 (m, 2H), 1.10-1.28 (m, 1H), 3.87 (d, J=7.2 Hz, 2H), 6.57 (d, J=10.2 Hz, 1H), 8.10 (dd, J=3.0 Hz & 2.4 Hz, 1H), 8.77 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[O:13]([CH2:21][CH2:22]O)[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:22][CH2:21][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
4-Tert-butoxyphenol (1 g, 6.02 mmole), 2-(t-butyldimethylsiloxy)ethanol (1.38 g, 7.83 mmole), and PPh3 (2.05 g, 7.82 mmole) were combined in toluene (30 mL) at RT. To this was added DIAD (1.52 mL, 7.82 mmole) slowly at RT. After stirring overnight the mixture was concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 0-10% EtOAc/hexanes) gave the title compound (1.7 g, 87%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 6.90 (d, J=8.8 Hz, 2 H); 6.80 (d, J=8.8 Hz, 2 H); 4.03-3.92 (m, 4 H); 1.30 (s, 9 H); 0.91 (s, 9 H); 0.10 (s, 6H).
Reaction SMILES: [S:1]([Cl:4])([Cl:3])=[O:2].CC(OC(C1C=CC(O)=CC=1)=O)CCCCCC.[CH2:23]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[S:1]([Cl:4])([Cl:3])=[O:2].[CH2:23]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([Cl:3])=[O:36])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCCCCCC(C)OC(=O)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Yield: 144.3 %

Procedure:
Preparation of optically active 4-(1-methylheptyloxycarbonyl)phenol Thionyl chloride (140 g, 1.18 mol) was added to 4-benzyloxybenzoic acid (220 g, 0.98 mol), followed by refluxing the mixture for about 2 hours, thereafter removing excess thionyl chloride under reduced pressure to obtain 4-benzyloxybenzoic chloride (210 g).
Reaction SMILES: N(C(C)C)[CH:2](C)C.[Li]CCCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16].CI.[NH4+].[Cl-]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:14][C:15]([C:17]1([CH3:2])[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCc2cccc(OC)c2C1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To iPr2NH (202 mg, 2.0 mmol) in THF (1.0 mL) was added BuLi (2.5 M, 0.8 mL, 2.0 mmol) at −78° C. After 10 minutes, 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester in THF (1.0 mL) was added and the reaction mixture turned yellow. Methyl iodide (568 mg, 4.0 mmol) and HMPA (1.0 mL) were added after 30 minutes. The reaction mixture was allowed to stir at −78° C. for 3 hours at ambient temperature before aqueous NH4Cl was added. The mixture was extracted with ethyl acetate (3×20 mL) and the combined extracts were dried over MgSO4 and purified by column chromatography to give 8-methoxy-2-methyl-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (170 mg, 84%).
Reaction SMILES: C(Cl)CCl.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:14]([OH:16])=O.CN.C(O)C.C1C=CC2N(O)N=[N:28][C:26]=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:26][NH:28][C:14]([C:6]1[NH:5][C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:16]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)c1cc2ccccc2[nH]1
Yield: 153.8 %

Procedure:
EDC (7.7 g, 40.3 mmol) was added to a solution of indole-2-carboxylic acid (5 g, 13.1 mmol), methylamine, 33% in ethanol (5.6 mL, 15.5 mmol), HOBT (4.1 g, 13.1 mmol) and DIPEA (2.1 mL, 12.4 mmol) in THF, anhydrous (45 mL) and stirred overnight. The crude mixture was evaporated in vacuo and chromatographed over silica eluting with methanol/dichloromethane (0-2%) to afford the title compound (3.51 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.43 (s, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.15 (t, J=8.2 Hz, 1H), 7.03 (s, 1H), 6.98 (t, J=7.9 Hz, 1H), 2.79 (d, J=4.7 Hz, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccnc(Oc3ccc(F)c(C(F)(F)F)c3)n2)cc1
Temperature: 75 °C
Yield: 192.9 %

Procedure:
To a solution of 0.60 g (2.87 mmol) of 2B in 15 ml of dimethylformamide was added 0.46 g of K2CO3 (3.3 mmol) and 0.60 g (3.3 mmol) of 4-fluoro-3-trifluoromethyl-phenol and the resulting mixture heated at 50° C. for 15 hr and 75° C. for 24 hrs. The cooled reaction mixture was poured into a separatory funnel containing 100 mL of ethyl acetate and washed with 2×50 mL water, 3×15 mL 2.5% NaOH solution, 1×30 mL brine, dried and evaporated in vacuuo to yield 1.95 g of a mobile yellow liquid. This material was filtered through a pad of silica and re-crystallized from heptane/ethyl acetate to give 0.49 g white crystalline solid (m.p. 69-74° C.; 48%)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].Cl.[CH3:32][NH:33][CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][N:33]([CH3:34])[C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)\[CH3:13])[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: C/C(=C\n1c2c(c3cc(N(C)C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Yield: 17.7 %

Procedure:
8-Chloro-2-methyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.100 g, 0.245 mmol), sodium tertbutoxide (0.283 g, 2.948 mmol), palladium acetate (0.010 g, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (0.031 g, 0.0735 mmol) were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Dry toluene (2 mL) was added under nitrogen atmosphere. Finally, di-methylamine hydrochloride (0.040 g, 0.490 mmol) was added and the contents heated at 100° C. overnight. The reaction mixture was filtered and precipitate washed with EtOAc (2×25 mL). The filtrate was concentrated under vacuum and purified by reverse phase chromatography to yield 15 mg of free base. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.90 (d, 2H), 8.38 (d, 2H), 7.99 (s, 1H), 7.80 (s, 1H), 7.56 (m, 2H), 4.50 (m, 2H), 3.90 (m, 1H), 3.70 (m, 1H), 3.38 (s, 6H), 3.22 (m, 2H), 3.18 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[CH2:14]1[CH:16]([CH:17](O)C#N)[CH2:15]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.[Cl-].[Na+].O.C(O)(=O)C>[CH:16]1([CH2:17][NH:1][N:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[CH:4][C:3]2=[O:13])[CH2:14][CH2:15]1
Reactant: Nn1c(=O)cc(O)c2ccccc21
Reactant: N#CC(O)C1CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=c1cc(O)c2ccccc2n1NCC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the suspension of 1-amino-4-hydroxyquinolin-2(1H)-one (1.033 g, 5.86 mmol) in methanol (58 mL) was added acetic acid (0.29 mL) and cyclopropylcarboxaldehyde (482 □L, 6.45 mmol) followed by the addition of sodium cyanoborohydride (744.6 mg, 11.85 mmol) at room temperature. The suspension was stirred at room temperature overnight and quenched with half saturated brine (100 mL) and sodium bicarbonate (425 mg, 5.06 mmol). The mixture was extracted with ethyl acetate (300 mL) and the organic layer was separated and washed with half saturated brine (2×50 mL). The combined aqueous layers were extracted with dichloromethane (2×100 mL). The combined organic solution was dried with magnesium sulfate, filtered and concentrated, to give (1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one) which was used without any purification. 1H NMR (300 MHz, DMSO-d6) δ 0.09 (m, 2 H) 0.40 (m, 2 H) 0.95 (m, 1 H) 2.70 (t, J=6.43 Hz, 2 H) 5.91 (s, 1 H) 6.10 (t, J=6.07 Hz, 1 H) 7.21 (m, 1 H) 7.62 (t, J=7.17 Hz, 1 H) 7.87 (m, 2 H) 11.42 (br s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>[OH-].[NH4+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Temperature: 210 °C

Procedure:
A stirred mixture of 4-(3-bromophenylamino)-6,7-dimethoxy-3-quinolinecarbonitrile (15.4 g, 40 mmol) and 100 g of pyridine hydrochloride was heated at 210° C. for 20 m, cooled to 0° C., treated with 100 ml of concentrated ammonium hydroxide, and concentrated to dryness. The residue was stirred with 1 L of water, and the resulting amber solid was filtered off, washed with water, and dried; mass spectrum (electrospray, m/e) M+H 356.1, 358.1.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:27]3[CH2:29][CH2:28]3)[C:16]3[O:23][C:20]4([CH2:22][CH2:21]4)[CH2:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:26]=2)=[CH:7][C:6]=1[F:30].CO.[OH-].[Na+]>ClCCl>[CH:27]1([C:15]2[C:16]3[O:23][C:20]4([CH2:22][CH2:21]4)[CH2:19][C:18]([CH3:25])([CH3:24])[C:17]=3[CH:26]=[C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]([F:30])[CH:7]=3)[CH:14]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#Cc3ccc(CC(=O)O)c(F)c3)cc21

Procedure:
Following general procedure L and using 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzeneacetic acid methyl ester (Compound 49, 0.096 g, 0.23 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by flash column chromatography over silica gel (230-400 mesh) using 15% methanol in dichloromethane as the eluent, the title compound was obtained as a solid (0.093 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21]NC.C=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH2:21])[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Product: C=C1COc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
A solution of 9.2 g of 6-benzyloxy-4-chromanone, dimethylamine hydrochloride and 1.3 g of paraformaldehyde in 100 ml of acetic acid was heated on a steam bath for 5 hours. The volatiles were evaporated in vacuo and the residue was purified on silica gel, eluting with CH2Cl2, to give 3.7 g of product, Rf (CH2Cl2)=0.5. 1H-NMR(CDCl3)delta(ppm): 4.95 (s, 2H), 5.05 (s, 2H), 5.55 (s, 1H), 6.30 (s, 1H), 6.80-7.60 (m, 8H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=[O:12].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:8]([O:7][CH2:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:8][CH:9]=2)[CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 206 %

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.C1([O:17][S:18](=O)(=[O:20])[NH2:19])C=CC=CC=1>O1CCOCC1.C(O)(C)C.C(OC(C)C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][O:10][S:18](=[O:20])(=[O:17])[NH2:19])[CH:2]=1
Reactant: OCCOc1cccnc1
Reactant: NS(=O)(=O)Oc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NS(=O)(=O)OCCOc1cccnc1
Reaction time: 18 h

Procedure:
A mixture of 4.9 g (0.035 mole) of 2(3-pyridinyloxy)ethanol (Preparation 18) and 8 g (0.046 mole) of sulfamic acid phenyl ester (Example 33) in 100 ml of dioxane was heated at reflux temperatue for 20 min. and the solvent then evaporated. The residue was triturated with 250 ml of acetone, filtered, and the filtrate acidified with a solution of anhydrous hydrogen chloride in isopropyl alcohol and the sticky brown precipitate collected. The brown solid was redissolved in 125 ml of methanol and diluted with 125 ml of ethanol. The solution was stirred with charcoal, filtered, and the filtrate partially evaporated to give a suspension. The suspension was diluted with isopropyl alcohol-isopropyl ether and filtered. The solid was dried at 50° C. for 18 hr and then at 70° C. for 18 hr in a vacuum oven. The yield was 4.5 g of solid title compound as the monohydrochloride, mp 156°-157° C.