Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[C:58]([CH3:59])=[CH:57][CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[CH3:52][C:53]1[C:58]([CH3:59])=[CH:57][CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: Cc1cccc(NC2CCNCC2)c1C
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.097 g, 0.00036 mol) in DMF (1 mL) was added DIPEA (0.233 g, 0.00180 mol), HOBt (0.053 g, 0.00036 mol) and EDCI.HCl (0.138 g, 0.00072 mol) at ambient temperature. After 2 minutes (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.12 g (77%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,3-dimethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 432.23 (M+1)+, 95.88%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.1 (s, 1H), 7.8 (t, 2H), 7.6 (m, 3H), 7.1 (s, 1H), 6.9 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.4 (m, 2H), 4.2 (s, 2H), 3.9 (d, 1H), 3.5 (s, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.2 (s, 3H), 2.0 (s, 5H), 1.4 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]=[C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[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>C(O)C.O1CCCC1.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(C2CCCCC2=Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)COc1cccc(C2CCCCC2Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methylene]cyclohexan-1-yl]phenoxy]acetate (300 mg) in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml) was added 10% palladium on carbon (50 mg). After being stirred for 4 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo to give ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]cyclohexan-1-yl]phenoxy]acetate (210 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[O:11]([C:13]#[N:14])[K]>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:13]([NH2:14])=[O:11])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Product: NC(=O)NNc1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 1061.3 %

Procedure:
To a solution of 1-(4-bromophenyl)hydrazine hydrochloride (25.0 g, 112 mmol) in H2O (500 mL) was added KOCN (730 mg, 9.01 mmol). The resulting solution was stirred at 40° C. overnight. After cooling to rt, the resulting solids were collected by filtration to obtain compound 11a as a grey solid (22.0 g, 84% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C7H8BrN3O: 230.0 (M+H). Found 230.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[ClH:3].[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:3])=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cn1
Solvent: ClC(Cl)Cl
Product: CSc1ccc(CCl)cn1
Product: Cl
Yield: 152.9 %

Procedure:
Thionylchloride (7.7 g) was added to 2-methylthiopyridine-5-methanol (7.8 g) (from the above referential example 1c) in chloroform (30 ml) at room temperature. After stirring for some time, the volatile matter was distilled off under reduced pressure to give 2-methylthio-5-chloromethyl pyridine hydrochloride (10.4 g) stoichiometrically ##STR27## The compounds synthesized the same way as in the above referential examples 1a, 1b, 1c are exemplified below. Method of referential example 1a: ##STR28## Method of referential example 1b: ##STR29## Method of referential example 1c: ##STR30##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[C:24]([F:27])[CH:23]=[CH:22][C:21]=3[CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: Cc1ccc(F)cc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3C)c(F)ccc2c1N
Yield: 57.8 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (300 mg, 0.80 mmol) and (2-methyl-5-fluorophenyl)boronic acid (246.8 mg, 1.60 mmol) were reacted to afford the title compound (164.7 mg, 58% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.48 (bs, 1H), 7.93 (d×d, J=5.3 Hz, J=9.4 Hz, 1H), 7.54 (apparent t, J=8.6 Hz, 1H), 7.30 (d×d, J=5.6 Hz, J=8.3 Hz, 1H), 6.99-7.09 (m, 2H), 3.44 (apparent q, J=7.0 Hz, 2H), 2.03 (s, 3H), 1.64 (apparent sextet, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=357 (M+H) HPLC 2.78 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:42]=[CH:41][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:26]=[C:25]([N:27]4[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38]CC)=[O:37])[CH:29]=[N:28]4)[CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:43].[Li+].Cl.[O:46]1CCOCC1>>[C:31]([OH:46])([C:32]([F:35])([F:34])[F:33])=[O:43].[C:1]1([CH2:7][CH2:8][C:9]2[CH:42]=[CH:41][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:26]=[C:25]([N:27]4[C:31]([C:32]([F:35])([F:33])[F:34])=[C:30]([C:36]([OH:38])=[O:37])[CH:29]=[N:28]4)[CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CCc4ccccc4)cc3)n2)c1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CCc4ccccc4)cc3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of the title compound from Example 1 Step C (27.0 mg, 0.048 mmol) in 1,4-dioxane (2 mL) was added lithium hydroxide (1.0 mL, 2.0 M aqueous, 2.0 mmol), and the resulting mixture was stirred at 60° C. After 15 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (30 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 544.4 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.25 (s, 1H), 8.14-8.07 (m, 2H), 7.74 (d, J=7.5 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.27-7.14 (m, 8H), 7.09 (t, J=8.0 Hz, 1H), 5.19 (s, 2H), 2.86 (app s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:18]2[C:17]([Cl:19])=[C:16]3[C:8](=[C:9]4[C:14](=[N:15]3)[CH:13]=[CH:12][CH:11]=[CH:10]4)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20]OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[C:18]2[C:17]([Cl:19])=[C:16]3[C:8](=[C:9]4[C:14](=[N:15]3)[CH:13]=[CH:12][CH:11]=[CH:10]4)[NH+:7]([CH3:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Clc1cccc2[nH]c3c4ccccc4nc-3c(Cl)c12
Solvent: Cc1ccccc1
Product: C[NH+]1C2=c3ccccc3=NC2=C(Cl)c2c(Cl)cccc21
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1-chloro-11-chloroquindoline from Example 50 (0.3 g, 1.0 mmol) in anhydrous toluene (12 mL) was added methyltriflate (0.25 mL, 206 mol %). The reaction mixture was stirred for 20 h at rt after which TLC analysis still showed starting material. Additional methyl triflate (100 mol %) and toluene (5 mL) were added. The reaction mixture was stirred overnight, filtered, washed with ether and dried to afford the crude title compound; MS (-FAB, m/z) 149.
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4Br)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>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.O>[N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=4[CH3:33])[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(N3CCC3)ncnn12
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3nc(C)n4ncnc(N5CCC5)c34)cnn2C)c(C)c1
Temperature: 150 °C

Procedure:
4-(Azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazine (200 mg, 0.574 mmol) was combined with (4-methoxy-2-methylphenyl)boronic acid (180 mg, 1.08 mmol), potassium phosphate dihydrate (98%, 571 mg, 2.25 mmol), tetrakis(triphenylphosphine)palladium(0) (99.9%, 65.9 mg, 0.057 mmol) and N,N-dimethylformamide (12 mL) and heated in a microwave reactor at 150° C. for 60 minutes. This reaction mixture was combined with crude reaction products from three other identical reactions, and poured into water. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, then with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic extracts were filtered and concentrated in vacuo. Purification via silica gel chromatography (Eluants: heptane/ethyl acetate/methanol mixtures, 90:15:10 followed by 60:30:10, 45:55:10, 30:70:10 ratios) provided the product as a solid. Combined yield: 508 mg, 1.30 mmol, 56%. LCMS m/z 390.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.08 (s, 3H), 2.26-2.35 (m, 2H), 2.60 (s, 3H), 3.69 (s, 3H), 3.79 (s, 3H), 3.8-4.2 (v br m, 4H), 6.72-6.76 (m, 2H), 7.17-7.24 (br m, 1H), 7.67 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=3[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:32]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=3[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(-c3ccc(OC)c(O)c3)coc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(-c3ccc(OC)c(O[Si](C)(C)C(C)(C)C)c3)coc2c1
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a solution of 14 (3.51 g, 12.9 mmol) in CH2Cl2 (30 mL), under nitrogen, was added Et3N (1.98 mL, 14.2 mmol) followed by DMAP (0.162 g, 14.2 mmol) and TBSCl (2.4 g, 14.2 mmol) at 0° C. The reaction mixture was stirred for 12 h allowing too reach room temperature. The reaction was quenched with water, the phases separated, and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic solutions were dried over MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, elution with hexanes) afforded 4.57 g (11.9 mmol, 92%) of the protected benzo[b]furan 15 as a colorless oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[N:11][CH:12]=1)([O-:18])=[O:17]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
In a 250 mL four-necked flask, sodiumhydride (60% in mineral oil, 4.16 g) was combined with DMF (60 mL). The suspension was cooled to 0° C. and 2,2,2-trifluoroethanol (10.4 g, [CAS Reg. No. 75-89-8]) was added dropwise over a period of 20 minutes to the cold suspension. The mixture was stirred for 1 hour at 0° C. Then, a solution of 2-chloro-5-nitropyridine (15 g, [CAS Reg. No. 4548-45-2]) in DMF (70 mL) was added dropwise over a period of 20 minutes to the cold reaction mixture. Stirring was continued for 10 minutes at 0° C. and for 2 hours at r.t. The reaction mixture was poured into ice/water and was then extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow solid (20.52 g, 93%). MS (EI, m/e): 222.0 [M+].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH3:14]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: COc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN(Cc1ccccc1)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a solution of ethyl N-benzyl-glycinate (34.1 g, 176 mmol) and m-anisaldehyde (11.0 g, 80.8 mmol) in methanol (500 mL) was added acetic acid (12.1 mL, 202 mmol) followed by sodium cyanoborohydride (3.4 g, 54 mmol). The mixture was stirred at ambient temperature for 2.5 hours whereupon LCMS analysis showed completion of the reaction. The solvent was removed on a rotary evaporator and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate to neutrality. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (CH2Cl2) gave 21.5 g (85% of [benzyl-(3-methoxy-benzyl)-amino]-acetic acid ethyl ester as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (m, 4H), 7.25 (m, 2H), 6.93 (m, 2H), 6.82 (d, J=9 Hz, 1H), 4.10 (q, J=7 Hz, 2H), 3.74 (s, 3H), 3.70 (s, 2H), 3.32 (s, 2H), 3.24 (s, 2H), 1.18 (t, J=7 Hz, 3H; MS (m/e) 314 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:23]1[CH:24]=[CH:25][C:20]([CH:18]=[CH:19][C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)=[CH:21][CH:22]=1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C(=Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2)c1ccncc1
Temperature: 102.5 °C
Yield: 72 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (295 mg, 1 mmol),4-vinylpyridine (0.135 mL, 1.25 mmol), palladium(II)acetate (7.2 mg,0.032 mmol), tri-o-tolylphosphine (38.7 mg, 0.127 mmol), and triethylamine (0.5 mL, 3.6 mmol) in anhydrous acetonitrile (0.5 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100 to 105° C. for 48 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated chloroform/methanol, 95:5), followed by recrystallization from acetone afforded the title compound (230 mg, 0.72 mmol, 72%): electrospray MS (m/z, relative intensity) 320 ([MH]+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:19][C:11]3([CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])C3)[CH:10]=2)[O:3]1.F[C:22](F)(F)S(OC1C[C@H]2[C@H]([C@@H]2C(OCC)=O)C=1)(=O)=O>>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:20])[O:3][B:4]([C:9]2[CH2:19][CH:11]3[CH:14]([CH:13]3[C:15]([O:17][CH2:18][CH3:22])=[O:16])[CH:10]=2)[O:5]1
Reactant: COC(=O)C1CC2(C=C(B3OC(C)(C)C(C)(C)O3)C2)C1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C(OS(=O)(=O)C(F)(F)F)C[C@@H]21
Product: CCOC(=O)C1C2C=C(B3OC(C)(C)C(C)(C)O3)CC21

Procedure:
The title compound was prepared in quantitative yield following the method described in step 2 for the preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene-2-carboxylate, using (±)-(1S,5S,6R)-ethyl 3-(((trifluoromethyl)sulfonyl)oxy)bicyclo[3.1.0]hex-2-ene-6-carboxylate as the reactant. 1H NMR (500 MHz, CHLOROFORM-d) δ 6.67 (q, J=2.0 Hz, 1H), 4.27-3.98 (m, 2H), 2.89-2.72 (m, 1H), 2.63-2.53 (m, 1H), 2.54-2.41 (m, 1H), 2.28 (td, J=6.2, 3.3 Hz, 1H), 1.33-1.15 (m, 16H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=2)[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]
Reactant: BrCc1ccc(I)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1c(OCc2ccc(I)cc2)ccc(C(C)=O)c1O
Reaction time: 48 h
Yield: 52.1 %

Procedure:
Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (6.54 g, 33.7 mmol) and cesium carbonate (13.2 g, 40.4 mmol) in acetone (500 mL) and stir. After 48 hours, pour the reaction into water and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a yellow solid (7.20 g, 52%): 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.09 (s, 2H), 6.43 (d, 1H), 7.15 (d, 2H), 7.57 (d, 1H), 7.73 (d, 2H), 12.74 (s, 1H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:6]([C:13]([O:15]CC)=[O:14])=[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])[N:8]=1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([S:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:6]([C:13]([OH:15])=[O:14])=[C:7]([C:9]([OH:12])([CH3:11])[CH3:10])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(SCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCSc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.3 %

Procedure:
1.00 g of ethyl 2-ethylthio-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 107(b)] and 256 mg of lithium hydroxide monohydrate were added to a mixture of 10 ml of water and 10 ml of dioxane. The mixture was then stirred at room temperature for 24 hours after which it was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in water, and then 6.1 ml of 1N aqueous hydrochloric acid were added. The oily matter which appeared was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 955 mg of the title compound as an amorphous powder.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:19])[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1.Cl>O1CCCC1.CCOCC>[O:19]=[C:9]1[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[C:3]([O:6][CH3:7])=[O:8]
Reactant: O=C1CCCC2CCCCC12
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CCC2CCCCC2C1=O

Procedure:
A suspension of sodium hydride (4.60 g, 115 mmol) in tetrahydrofuran (20 mL) was treated with dimethyl carbonate (8.29 mL, 99 mmol), heated to reflux under nitrogen, treated dropwise with a solution of octahydronaphthalen-1(2H)-one (Aldrich cat#115063, mixture of trans (major) and cis (minor), 5 g, 32.8 mmol) in tetrahydrofuran (20 mL) over 5 minutes, and heated to reflux overnight. The mixture was cooled, diluted with ether (300 mL) and treated with 1 M hydrochloric acid (150 mL). The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined ether layers were washed with brine, dried (magnesium sulfate), filtered and concentrated to provide the desired product that was not purified, but used as is in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=1)[O:9][C:8]([CH3:20])([CH3:19])[CH2:7][C:6]2([CH3:22])[CH3:21])#[CH:2].[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][C:28]=1[F:34].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=2)[O:9][C:8]([CH3:20])([CH3:19])[CH2:7][C:6]3([CH3:22])[CH3:21])=[CH:29][C:28]=1[F:34]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cc(C#C[Si](C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(C#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure J and using 6-ethynyl-8-trimethylsilanylethylnyl-2,2,4,4-tetramethyl chroman (Compound 37, 0.1 g, 0.32 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (see U.S. Pat. No. 6,252,090, 0.095 g, 0.32 mmol), triethyl amine, copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.071 g, 0.1 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 4-10% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.11 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([O:10][CH:9]2[CH2:8][NH:7][CH2:6][C:5]3[S:11][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Cc1cc2c(s1)CNCC2O
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(s1)CNCC2Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 8) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.