Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].Cl>N1C=CC=CC=1>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:27][C:28](=[O:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C1CCCC1
Yield: 99.7 %

Procedure:
To 2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.8 g, 7.5 mmol) in anhydrous pyridine (20 mL) at room temperature under nitrogen was added dropwise acetic anhydride (0.92 mL, 9.8 mmol). The reaction mixture was placed in the refrigerator. After 41 h the reaction was diluted and acidified with 10% aqueous hydrochloric acid to a pH of 1. The mixture was extracted with diethyl ether (500 mL), and the diethyl ether layer was washed with 5% aqueous hydrochloric acid (100 mL), twice with water (100 mL), brine (100 mL), and then dried (MgSO4). Concentration under reduced pressure gave the title compound as a white solid (3.1 g, 98%): (DMSO-d6) δ 8.48 (s, 1 H), 7.97 (d, 1 H), 7.47-7.43 (m, 1 H), 7.38-7.36 (m, 2 H), 7.28 (s, 1 H), 7.19 (d, 2 H), 3.14 (quintet, 1 H), 2.40 (s, 3 H), 2.37 (s, 3 H), 1.99-1.91 (m, 2 H), 1.69-1.40 (m, 6 H), 1.56 (s, 3 H). MS(EI), [M+] 414. Anal. Calc. for C27H26O2S: C, 78.23, H, 6.32, N, 0.00. Found: C, 77.68, H, 6.39, N, 0.04.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:13]([CH2:19][N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(CCc2ccccc2)C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N(CCc1ccccc1)Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-{4-bromo-2-[(methoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-phenyl)-acetic acid methyl ester in THF and MeOH was added lithium hydroxide, and the reaction was stirred overnight at room temperature. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were concentrated and purified by preparative HPLC to give the title compound. M+H=498.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:49]12[CH2:56][CH2:55][CH:52]([CH2:53][CH2:54]1)[C@@H:51](O)[CH2:50]2>C1COCC1>[O:16]=[C:15]([O:17][C@@H:51]1[CH:52]2[CH2:55][CH2:56][N:49]([CH2:54][CH2:53]2)[CH2:50]1)[CH:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCOC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C=CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 2-(3-(allyloxycarbonyl)phenylamino)-2-phenylacetic acid (I3) (2.69 g, 8.64 mmol) in dry THF (80 ml), were added DCC (3.57 g, 17.3 mmol) and HOBt (2.65 g, 17.3 mmol). After 30 minutes, (R)-quinuclidin-3-ol (3.30 g, 25.9 mmol) was added and reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the crude residue was purified by flash-chromatography (DCM/MeOH=97/3+0.3% NH4OH) to obtain allyl 3-(2-oxo-1-phenyl-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (2.40 g, 66.1% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11](Cl)(=[O:13])=[O:12])=[CH:3]1.[NH3:15]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([NH2:15])(=[O:13])=[O:12])=[CH:3]1
Reactant: N
Reactant: Cn1cc(S(=O)(=O)Cl)c2ccccc21
Solvent: C1CCOC1
Product: Cn1cc(S(N)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-methyl-1H-indole-3-sulfonyl chloride (0.86 g, 3.75 mmol) in THF (40 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water; the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain 1-methyl-1H-indole-3-sulfonic acid amide (0.64 g) as a yellowish solid. MS (ISN): m/e 209.4 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](P(=O)(OCC)OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution containing 164 mg of 5-(3,5-dichloro-phenylsulphanyl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 103 mg of diethyl benzylphosphonate and 27 mg of sodium hydride (60% in mineral oil) in 5 ml of anhydrous tetrahydrofuran was stirred under nitrogen at rt for 16 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°-60° C. (1:10) for the elution to give 162 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole as a pale yellow solid. Mass spectrum (EI) m/z 436 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:16]3[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:13][C@@H:11]1[CH2:12][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](=[O:24])[N:25]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)=[C:16]3[CH:15]=2)[CH2:10]1)(=[O:54])=[O:53]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](OS(C)(=O)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-33) (150 mg, 0.26 mmol) in DCM (anhyd, 2 mL) at 0° C. was added triethylamine (0.070 mL, 0.5 mmol) followed by dropwise addition of methanesulfonyl chloride (28 μL, 0.36 mmol). After stirring 2 hours at room temperature the reaction mixture was concentrated under reduced pressure. The resulting solid was taken up in EtOAc and washed twice with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford (3R,5R)-1-(3-(bis(4-methoxybenzyl)carbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-5-(3-fluorophenyl)pyrrolidin-3-yl methanesulfonate (I-34), which was used without further purification. MS m/z 659.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:15][CH2:16][C:17](Br)=[O:18]>O1CCOCC1>[Br:15][CH2:16][C:17]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:18]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A solution of 4-aminobenzonitrile (5.0 g, 42.3 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (8.53 g, 3.7 mL, 42.3 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a pale brown solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 7.78 g (77%) of the title compound as a pale brown solid, mp 166°-168° C.: 1H NMR (DMSO-d6) δ10.81 (s, 1H), 7.81-7.74 (m, 4H), 4.08 (s, 2H); 13C NMR (DMSO-d6) δ165.60, 142.75, 133.39, 119.28, 118.89, 105.60, 30.17; MS (EI, m/z) 238 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[OH:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(O)c(F)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)c(F)c3)ccn2c1=O
Yield: 76.1 %

Procedure:
Methyl 8-(3-fluoro-4-hydroxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-fluoro-4-hydroxyphenyl)boronic acid (64.1 mg, 0.41 mmol). The residue was rinsed with DCM and dried in a vacuum stove to afford the title compound as a yellow solid (95 mg, 76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22](=[O:23])[O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccncc2)cc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-pyridinyl)aniline (50 mg) in dichloromethane (1.50 mL) and pyridine (356.4 μL) was added dropwise benzyloxycarbonyl chloride (75.5 μL) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was concentrated in vacuo and water (10 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (15 mL) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine, then dried and concentrated. The residual solid was triturated with diisopropylether (2.0 mL) to give benzyl [4-(4-pyridinyl)phenyl]carbamate (70.3 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].[CH2:27]([OH:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:30][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: CCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 168 h

Procedure:
Ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (363 mg) was added to a solution of potassium tert.-butoxide (427 mg) in ethylene glycol (7 ml) and stirred at 100° C. for 7 days. The reaction mixture was then poured onto ice/water and extracted with ethyl acetate. The crude product was purified by chromatography over silicagel with DCM/MeOH=9/1 to give ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (310 mg) as a white powder. LC-MS: tR: 3.47, [M+H]+: 338.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([C:13](Cl)([Cl:15])[Cl:14])[O:8][C:9]2=[O:12])=[CH:5][CH:4]=1>[Zn].C(O)(=O)C>[Cl:14][C:13]([Cl:15])=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=1[C:9]([OH:12])=[O:8]
Reactant: COc1ccc2c(c1)C(=O)OC2C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(C=C(Cl)Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A 100 mL round-bottomed flask containing a stirring bar was charged with 6-methoxy-3-(trichloromethyl)isobenzofuran-1(3H)-one (3.09 g, 10.94 mmol) and glacial acetic acid (40.0 mL). Zinc dust (2.86 g, 43.76 mmol) was added in small portions over 30 min. to the stirred reaction mixture. The reaction was left stirring at room temperature for further 30 min. and then heated at reflux for 1 h. It was filtered hot over a pad of Celite and the filtrates were diluted with water. The precipitate formed was collected by filtration and recrystallised from EtOH/H2O to give 2-(2,2-dichlorovinyl)-5-methoxybenzoic acid as white needles (1.74 g, 64%). Spectral data for this compound were consistent with those in the literature. M.p. 164-166° C. (lit. m.p. 167-168° C.); 1H NMR (400 MHz, DMSO-d6): δ=13.31 (br. s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.47-7.39 (m, 2H), 7.21 (dd, J=8.7 Hz, J=2.2 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][N:9]=1)([OH:7])[CH3:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C1COCC1.O>[F:19][C:4]([F:3])([F:18])[C:5]([O:7][S:21]([CH3:20])(=[O:23])=[O:22])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH3:17])=[CH:10][N:9]=1)[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C(C)(O)C(F)(F)F)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C(C)(OS(C)(=O)=O)C(F)(F)F)nc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 0.213 g (8.44 mmol) sodium hydride in 6 ml dry THF, 1.06 g (4.22 mmol) 1,1,1-trifluoro-2-(5-methoxymethoxy-pyridin-2-yl)-propan-2-ol (dissolved in 4.9 ml dry THF) was added dropwise at 0° C. After completion of the addition, stirring was continued for 3 h at room temperature. Then methanesulfonyl chloride (dissolved in 7.3 ml dry THF) was added at room temperature and stirring was continued for another 2 h. Then water and sat. NaHCO3 soln. were added. This mixture was extracted 2 times with EtOAc. The combinded organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1.7 g of the title compound, which was used directly in the next step. LCMS (method L): tR=0.96 min, M+H=330.
Reaction SMILES: [OH:1][C@H:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1.O>CN(C=O)C>[Si:32]([O:1][C@H:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C[C@H]1CCc2cc(I)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 27 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A reaction mixture containing tert-butyl (2S)-2-hydroxy-3-phenoxypropyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 81, 8.625 mmol, 1.0 eq.), tert-butyldimethylsilyl chloride (10.35 mmol, 1.2 eq.), and imidazole (21.5625 mmol, 2.5 eq.) in anhydrous DMF (18 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=100:5). The product was obtained as a colorless oil in 97% yield. MH+=654.0, retention time (LC-MS)=5.29 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][CH:8]=1.O1CCC[CH2:32]1.CI>>[CH3:32][N:6]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:29][CH2:28][CH2:27][C@@:15]3([C:19](=[O:20])[N:18]([CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH2:17][CH2:16]3)[CH2:14]2)=[CH:9][CH:8]=1)[C:5](=[O:30])[O:4][CH3:3]
Reactant: C1CCOC1
Reactant: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)N(C)c1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (1.6 mg, 0.000041 mol) was added to a solution of methyl{4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate (8.0 mg, 0.000021 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) at rt. After stirring for 5 min., methyl iodide (2.6 μL, 0.000041 mol) was added and the reaction mixture was stirred for 1 h at rt. The crude product was purified by prep-HPLC. LC-MS: 402.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:10]1[C:9](=[O:14])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:15]([F:16])([F:17])[F:18])[CH:4]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: BrBr
Reactant: Cc1ccc(C2CCCCC2=O)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CCCC(Br)C2=O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 104.4 %

Procedure:
2-(4-Methyl-3-trifluoromethyl-phenyl)-cyclohexanone (50 mg, 0.20 mmol) was dissolved in chloroform (1 mL). To this solution bromine (32.7 mg, 0.21 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the title compound (70 mg) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:23][N:24]([CH3:26])[CH3:25]
Reactant: COC(OC)N(C)C
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Yield: 90.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3,4-dihydro-quinazolin-4-one (1.0 g, 3.46 mmol) and dimethylformamide dimethyl acetal (0.92 mL, 6.92 mmol) in dimethylformamide (4 mL) was heated to 140° C. for 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure. The dark residue was triturated with methanol and the bright yellow crystalline solid which formed was collected and dried to give 1.075 g (90%) of 3-(2-chloro-phenyl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one which had: mp 210-211° C.; 1H NMR δ 7.86 (d, J=12.3 Hz, 1 H), 7.79 (dd, J=3, 8.5 Hz, 1 H), 7.61-7.54 (m, 1 H), 7.51-7.29 (m, 5 H), 4.06 (d, J=12.3 Hz, 1 H), 2.80 (br s, 6 H). Analysis calculated for C18H15ClFN3O: C, 62.89; H, 4.40; N, 12.22. Found: C, 62.75; H, 4.28; N, 12.29.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([C:13]2[C:24]([CH2:25]O)=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([C:13]2[C:24]([CH2:25][C:5]#[N:6])=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: OCc1c(-c2ccccc2)nn2ccc3occc3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1c(-c2ccccc2)nn2ccc3occc3c12
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (460 μL, 3.63 mmol) and trimethylsilyl cyanide (645 μL, 4.84 mmol) in dichloromethane (12 mL) was added a solution of (2-phenylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (320 mg, 1.21 mmol) in dichloromethane (12 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred for 2 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (240 mg, yield 73%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][C:26]([CH2:30][CH3:31])=[C:27]([CH3:29])[N:28]=1>C(O)C>[CH2:30]([C:26]1[S:25][C:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])=[N:28][C:27]=1[CH3:29])[CH3:31]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: CCc1sc(N)nc1C
Solvent: CCO
Product: CCc1sc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)nc1C
Yield: 63 %

Procedure:
N-(5-Ethyl-4-methyl-2-thiazolyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-5-ethyl-4-methyl-thiazole. Yield: 63% of theory; m.p. 253°-255° C (decomp.; from ethanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(CCC(=O)OC(C)(C)C)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 6-(3-tert-butoxy-3-oxopropyl)imidazo[1,2-a]pyridine-3-carboxylate (71) (400 mg, 1.26 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 4 mL) was heated at 60° C. for 30 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(3-(tertbutoxy)-3-oxopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (72) was dried and used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1H), 8.20 (s, 1H), 7.72 (dd, J=0.8, 9.2 Hz, 1H), 7.50 (dd, J=1.6, 9.2 Hz, 1H), 2.91 (t, J=6.8 Hz, 2H), 2.60 (t, J=7.2, 2 H), 1.33 (s, 9H). MS m/z 291.13 (M+1)+.